* 300169

APOPTOSIS-INDUCING FACTOR, MITOCHONDRIA-ASSOCIATED, 1; AIFM1


Alternative titles; symbols

APOPTOSIS-INDUCING FACTOR; AIF
PROGRAMMED CELL DEATH 8; PDCD8


HGNC Approved Gene Symbol: AIFM1

Cytogenetic location: Xq26.1     Genomic coordinates (GRCh38): X:130,129,362-130,165,841 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Xq26.1 Combined oxidative phosphorylation deficiency 6 300816 XLR 3
Cowchock syndrome 310490 XLR 3
Deafness, X-linked 5 300614 XLR 3
Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy 300232 XLR 3

TEXT

Description

The AIFM1 gene encodes a mitochondrial flavin adenine dinucleotide (FAD)-dependent oxidoreductase that plays a role in oxidative phosphorylation (OxPhos) and redox control in healthy cells. After mitochondrial outer membrane permeabilization, which is a feature of most, if not all, apoptotic pathways, AIFM1 is released from mitochondria and translocates to the nucleus, where it mediates nuclear features of apoptosis such as chromatin condensation and large-scale DNA degradation (summary by Joza et al., 2009).


Cloning and Expression

Susin et al. (1999) identified and cloned an apoptosis-inducing factor, AIF, that is sufficient to induce apoptosis of isolated nuclei. They cloned the mouse homolog of AIF, which has 92% amino acid identity to the human protein. The full-length proteins of both mouse and human contain 2 mitochondrial localization sequences and 2 putative nuclear localization signals. Mature mouse AIF has a molecular mass 57 kD that shares homology with the bacterial oxidoreductases, whereas the mouse precursor AIF transcript is 67 kD. AIF was normally confined to the mitochondrial intermembrane space, but translocated to the nucleus when apoptosis is induced. Recombinant AIF caused chromatin condensation and large scale fragmentation of DNA in isolated HeLa cell nuclei. It induced purified mitochondria to release the apoptogenic proteins cytochrome c (123970) and caspase-9 (602234). Microinjection of AIF into the cytoplasm of intact cells induced condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of the effects were prevented by pretreatment with a caspase inhibitor. Overexpression of BCL2 (151430), which controls the opening of mitochondrial permeability transition pores, prevented the release of AIF from the mitochondrion, but did not affect its apoptogenic activity. Susin et al. (1999) concluded that AIF is the principal mitochondrial factor causing nuclear apoptosis. They postulated that the caspases, DFF/CAD (601883), and AIF are engaged in complementary cooperative or redundant pathways that lead to nuclear apoptosis.

Ghezzi et al. (2010) identified human AIF as a 62-kD mature mitochondrion-specific protein that binds FAD and attaches by an N-terminal transmembrane domain to the inner mitochondrial membrane, where is functions as an NADH oxidase. Upon apoptogenic stimuli, the 57-kD soluble AIF containing 512 amino acids is released by proteolytic cleavage and translocates from the mitochondria to the nucleus, where it binds to chromosomal DNA and induces chromatin condensation and DNA fragmentation by attracting and activating a set of endonucleases. The full-length human precursor protein is a 67-kD polypeptide and contains 613 amino acids. After mitochondrial import, cleavage of a 54-amino acid mitochondrial targeting sequence results in the 62-kD mature protein containing 559 amino acids.

Zong et al. (2015) found ubiquitous expression of the Aifm1 gene in the mouse inner ear, especially in the cytoplasm of inner and outer hair cells and spiral ganglion neurons, consistent with a role in normal auditory function.


Mapping

By its inclusion within a mapped clone (GenBank Z81364), Susin et al. (1999) mapped the AIFM1 gene to chromosome Xq25-q26.

Gross (2013) mapped the AIFM1 gene to chromosome Xq26.1 based on an alignment of the AIFM1 sequence (GenBank AF100928) with the genomic sequence (GRCh37).


Gene Function

Programmed cell death is a fundamental requirement for embryogenesis, organ metamorphosis, and tissue homeostasis. In mammals, release of mitochondrial cytochrome c leads to cytosolic assembly of the apoptosome--a caspase activation complex involving APAF1 (602233) and caspase-9 that induces hallmarks of apoptosis. There are, however, mitochondrially regulated cell death pathways that are independent of APAF1/caspase-9. Like cytochrome c, AIF is localized to mitochondria and released in response to death stimuli. Joza et al. (2001) showed that genetic inactivation of AIF renders embryonic stem cells resistant to cell death after serum deprivation. Moreover, AIF is essential for programmed cell death during cavitation of embryoid bodies--the very first wave of cell death indispensable for mouse morphogenesis. AIF-dependent cell death displays structural features of apoptosis, and can be genetically uncoupled from APAF1 and caspase-9 expression. Joza et al. (2001) concluded that their data provide genetic evidence for a caspase-independent pathway of programmed cell death that controls early morphogenesis.

Yu et al. (2002) demonstrated that poly(ADP-ribose) polymerase-1 (PARP1; 173870) activation is required for translocation of AIF from the mitochondria to the nucleus and that AIF is necessary for PARP1-dependent cell death. N-methyl-N-prime-nitro-N-nitrosoguanidine, hydrogen peroxide, and NMDA induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP1-dependent cytotoxicity. Yu et al. (2002) concluded that their data support a model in which PARP1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death.

Andrabi et al. (2006) and Yu et al. (2006) demonstrated that the product of PARP1 activity, poly(ADP-ribose) (PAR) polymer, mediates PARP1-induced cell death. Yu et al. (2006) showed that PAR polymer induced the release of Aif from mitochondria in mouse cortical neurons and induced its translocation to nuclei. They also showed that poly(ADP-ribose) glycohydrolase (PARG; 603501) prevented Parp1-dependent Aif release. Furthermore, cells with reduced levels of Aif were resistant to PARP1-dependent cell death and PAR polymer cytotoxicity.

Joza et al. (2009) provided a review of AIFM1 functional and animal model studies and discussed its role in caspase-independent cell death pathways, mitochondrial metabolism and redox control, and obesity and diabetes.


Molecular Genetics

Combined Oxidative Phosphorylation Deficiency 6

In 2 Italian male first cousins, born of monozygotic twin sisters and unrelated fathers, with combined oxidative phosphorylation deficiency resulting in a severe mitochondrial encephalomyopathy (COXPD6; 300816), Ghezzi et al. (2010) identified a hemizygous deletion in the AIFM1 gene (300169.0001). Both had onset in the first year of life of psychomotor regression, muscle weakness and atrophy, lack of further development, and abnormal signals in the basal ganglia. One died at age 16 months, and the other was tetraplegic and wheelchair-bound with an inability to communicate at age 5 years. In vitro studies showed that the AIFM1 mutation resulted in destabilization of the inner mitochondrial membrane with subsequent damage to respiratory chain structure and activities. In addition, the mutation resulted in impaired control of mitochondrion-derived programmed cell death.

In 2 brothers with COXPD6, Berger et al. (2011) identified a hemizygous mutation in the AIFM1 gene (G308E; 300169.0012). The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; the unaffected mother was a carrier. Functional studies of the variant and studies of patient cells were not performed.

In 2 male first cousins, born of Italian sisters, with COXPD6, Diodato et al. (2016) identified a hemizygous missense mutation in the AIFM1 gene (G338E; 300169.0013). The mutation, which was found by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 142) or ExAC databases. Western blot analysis of patient cells showed decreased levels of the AIFM1 protein compared to controls.

Cowchock Syndrome/X-Linked Charcot-Marie-Tooth Disease 4 With or Without Cerebellar Ataxia

In affected members of the original family with Cowchock syndrome (310490), also known as X-linked recessive Charcot-Marie-Tooth disease-4 (CMTX4), reported by Cowchock et al. (1985), Rinaldi et al. (2012) identified a hemizygous mutation in the AIFM1 gene (E493V; 300169.0002). The mutation was identified by exome sequencing in 1 affected family member and confirmed by Sanger sequencing to segregate with the disorder within the family. Studies of the recombinant E493V mutant protein showed some structural changes that altered the redox properties of the protein without affecting activity of the respiratory chain complexes. Patient muscle biopsy showed an increased number of apoptotic cells compared to controls, suggesting activation of the caspase-independent cell death pathway. The phenotype was characterized by early-onset axonal sensorimotor neuropathy associated in some patients with hearing loss and cognitive impairment. The findings expanded the spectrum of disorders associated with AIFM1 mutations.

In a 39-year-old man with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; 310490), Ardissone et al. (2015) identified a hemizygous missense mutation in the AIFM1 gene (G262S; 300169.0014). The mutation, which was found by sequencing of a panel of genes involved in mitochondrial disorders, was inherited from the unaffected mother. Western blot analysis of patient fibroblasts showed decreased amounts of the protein, suggesting instability.

In 7 affected males from a multigenerational Irish family with CMTX4 with cerebellar ataxia, Bogdanova-Mihaylova et al. (2019) identified a hemizygous missense mutation in the AIFM1 gene (M340T; 300169.0015). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.

X-linked Deafness 5

In affected members of 5 unrelated Chinese families with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified 5 different missense mutations in the AIFM1 gene (300169.0003-300169.0007). Mutations in the first 2 families were found by whole-exome sequencing and confirmed by Sanger sequencing. Screening of this gene identified the same or additional hemizygous mutations in 11 (10%) of 93 men with sporadic auditory sensory disorder. The mutations segregated with the disorder in the families, and female carriers were unaffected. Of the 11 different missense variants identified, most occurred in the NADH and second FAD domains of the protein, which are essential for FAD-dependent NADH oxidoreductase. Functional studies of the variants were not performed.

X-linked Spondyloepimetaphyseal Dysplasia With Hypomyelinating Leukodystrophy

In 4 Polish brothers (family 2) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), Mierzewska et al. (2017) identified a hemizygous missense mutation in exon 7 of the AIFM1 gene (D237G; 300169.0008). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing and linkage analysis, segregated with the disorder in the family. The unaffected mother was a heterozygous carrier. The same heterozygous D237G mutation was found in an obligate carrier female from an unrelated family (family 1) in which 3 deceased males had a similar disorder (Bieganski et al., 1999). The mutation was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of 1,343 individuals from the Polish population. Functional studies of the variant and studies of patient cells were not performed.

In 12 affected males from 6 unrelated families with SEMDHL, Miyake et al. (2017) identified hemizygous mutations in the AIFM1 gene (see, e.g., 300169.0008-300169.0011). The variants, which were found by whole-genome or whole-exome sequencing, either occurred de novo or were inherited from unaffected mothers. All the mutations clustered around exon 7, suggesting a specific functional impairment, and in silico analysis predicted that the variants would result in splicing defects. Analysis of fibroblasts and transdifferentiated osteoblasts derived from some patients showed decreased AIFM1 mRNA and protein levels compared to controls. Miyake et al. (2017) concluded that AIFM1 plays a role in bone metabolism and myelination, which would account for the unique constellation of features in this disorder.


Animal Model

Harlequin (Hq) mutant mice have progressive degeneration of terminally differentiated cerebellar and retinal neurons. Klein et al. (2002) identified the Hq mutation as a proviral insertion in the Aif gene, causing an approximately 80% reduction in Aif expression. Mutant cerebellar granular cells were susceptible to exogenous and endogenous peroxide-mediated apoptosis, but could be rescued by Aif expression. Overexpression of Aif in wildtype granule cells further decreased peroxide-mediated cell death, suggesting that AIF serves as a free radical scavenger. In agreement, dying neurons in aged Hq mutant mice showed oxidative stress. In addition, neurons damaged by oxidative stress in both the cerebellum and retina of Hq mutant mice reentered the cell cycle before undergoing apoptosis. The results of Klein et al. (2002) provided a genetic model of oxidative stress-mediated neurodegeneration and demonstrated a direct connection between cell cycle reentry and oxidative stress in the aging central nervous system.

Wang et al. (2002) reported that inactivation of the C. elegans AIF homolog WAH-1 by RNA interference delayed the normal progression of apoptosis and caused a defect in apoptotic DNA degradation. WAH-1 localized in C. elegans mitochondria and was released into the cytosol and nucleus by the BH3-domain protein EGL1 (606266) in a caspase (CED3)-dependent manner. In addition, WAH-1 associated and cooperated with the mitochondrial endonuclease CPS6-endonuclease G (600440) to promote DNA degradation and apoptosis. Thus, AIF and EndoG define a single, mitochondria-initiated apoptotic DNA degradation pathway that is conserved between C. elegans and mammals.

Brown et al. (2006) found that inactivating Aif in the early mouse embryo had no effect on the apoptosis-dependent process of cavitation in embryoid bodies and apoptosis associated with embryonic neural tube closure, indicating that Aif function is not required for apoptotic cell death in early mouse embryos. By embryonic day 9, loss of Aif function caused abnormal cell death, presumably due to reduced mitochondrial respiratory chain complex-1 activity. Because of this cell death, Aif-null embryos failed to increase significantly in size after embryonic day 9. However, patterning continued on an essentially normal schedule, such that embryonic day-10 Aif-null embryos with only about 10% of the normal cell number had the same somite number as their wildtype littermates. Brown et al. (2006) concluded that pattern formation in the mouse can occur independent of embryo size and cell number.

In the rd1 mouse model of retinitis pigmentosa (see 180072) and an in vitro cellular model, Sanges et al. (2006) found that both Aif and caspase-12 (CASP12; 608633) translocated to the nucleus of dying photoreceptors. Only differentiated rd1 photoreceptors underwent apoptosis, and apoptosis was never observed in amacrine, bipolar, or horizontal retinal neurons. Translocation of both apoptotic factors required increased intracellular calcium, and calpain (see CAPN1; 114220) inhibitors interfered with Aif and Casp12 activation and rd1 photoreceptor apoptosis. Knockdown of Aif or Casp12 by interfering RNA showed that Aif played a major role in this apoptotic event and that Casp12 had a reinforcing effect.


ALLELIC VARIANTS ( 17 Selected Examples):

.0001 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6

AIFM1, 3-BP DEL, 601AGA
  
RCV000012302

In 2 Italian male first-cousins, born of monozygotic twin sisters and unrelated fathers, with combined oxidative phosphorylation deficiency resulting in a severe mitochondrial encephalomyopathy (COXPD6; 300816), Ghezzi et al. (2010) identified a hemizygous 3-bp deletion (601delAGA) in the AIFM1 gene, resulting in the deletion of arg201. Both had onset in the first year of life of psychomotor regression, muscle weakness and atrophy, lack of further development, and abnormal signals in the basal ganglia. One died at age 16 months, and the other was tetraplegic and wheelchair-bound with an inability to communicate at age 5 years. In silico analysis indicated that arg201 residue is part of a hairpin that forms the FAD-binding pouch and confers conformational stability to the flavoprotein. Thus, deletion of arg201 probably perturbs the functional properties of both oxidized and reduced forms of AIF. In vitro studies showed that the lifetime of the FADH2-NAD complex formed by mutant mitochondrial AIF was shorter than that observed with wildtype. The mutant protein also had increased susceptibility to proteolytic cleavage, indicating that it is a structurally unstable variant. The mutant protein also showed higher DNA binding affinity and potential ability to cause DNA damage compared to wildtype. Approximately 75% of mutant cells versus 23% of control cells showed mitochondrial fragmentation under galactose treatment, suggesting that cells containing the mutant are more sensitive to apoptotic stimuli than control cells. Mitochondrial fragmentation was associated with impaired oxidative phosphorylation. Riboflavin treatment of cells with the mutant protein showed a recovery of the filamentous network and improvement in cell viability, which corresponded to some clinical improvement seen in 1 of the patients with the mutation. Overall, the studies showed that the AIFM1 mutation resulted in destabilization of the inner mitochondrial membrane with subsequent damage to respiratory chain structure and activities. In addition, the mutation resulted in impaired control of mitochondrion-derived programmed cell death.


.0002 COWCHOCK SYNDROME

AIFM1, GLU493VAL
  
RCV000032801

In affected members of the original family with Cowchock syndrome (310490) reported by Cowchock et al. (1985), Rinaldi et al. (2012) identified a hemizygous 1478A-T transversion in exon 14 of the AIFM1 gene, resulting in a glu493-to-val (E493V) substitution at a highly conserved residue. The mutation was identified by exome sequencing in 1 affected family member and confirmed by Sanger sequencing to segregate with the disorder within the family. The mutation was not found in 712 control individuals. Studies of the recombinant E493V mutant protein showed that it had a lower Km for NADH compared to wildtype, and was reduced by NADH 4-fold faster than wildtype. The charge-transfer complex had a shorter half-life than wildtype, but retained its ability to dimerize upon reduction with NADH. The mutant protein altered the redox state without affecting respiratory chain complex activity. Patient muscle biopsy showed an increased number of apoptotic cells compared to controls, suggesting activation of the caspase-independent cell death pathway. The phenotype was characterized by early-onset axonal sensorimotor neuropathy associated in some patients with hearing loss and cognitive impairment.


.0003 DEAFNESS, X-LINKED 5

AIFM1, ARG451GLN
  
RCV000202363...

In affected male members of a large Chinese family (family AUNX1) with X-linked deafness-5 (DFNX5; 300614), originally reported by Wang et al. (2006), Zong et al. (2015) identified a hemizygous c.1352G-A transition (c.1352G-A, NM_004208.3) in exon 13 of the AIFM1 gene, resulting in an arg451-to-gln (R451Q) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project or Exome Sequencing Project databases or in 500 Chinese controls. Functional studies of the variant were not performed.


.0004 DEAFNESS, X-LINKED 5

AIFM1, LEU344PHE (rs184474885)
  
RCV000149862...

In 2 Chinese brothers (family 0223) with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified a hemizygous c.1030C-T transition (rs184474885) in exon 10 of the AIFM1 gene, resulting in a leu344-to-phe (L344F) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was annotated in the dbSNP (build 141) database at a very low frequency (0.0005), but was not found in 500 Chinese controls. Screening for AIFM1 mutations in 93 unrelated patients with sporadic auditory neuropathy revealed that 3 additional unrelated patients carried the L344F mutation. Functional studies of the variant were not performed.


.0005 DEAFNESS, X-LINKED 5

AIFM1, THR260ALA
  
RCV000202359

In affected male members of a large Chinese family (family 7170) with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified a hemizygous c.778A-G transition (c.778A-G, NM_004208.3) in exon 7 of the AIFM1 gene, resulting in a thr260-to-ala (T260A) substitution. The variant was not found in the Exome Sequencing Project or 1000 Genomes Project databases or in 500 Chinese controls. Functional studies of the variant were not performed.


.0006 DEAFNESS, X-LINKED 5

AIFM1, ARG422TRP
  
RCV000149864...

In 3 affected males from a Chinese family (family 2724) with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified a hemizygous c.1264C-T transition (c.1264C-T, NM_004208.3) in exon 12 of the AIFM1 gene, resulting in an arg422-to-trp (R422W) substitution. Two unrelated patients with sporadic disease were also found to carry the R422W mutation. The variant was not found in the Exome Sequencing Project or 1000 Genomes Project databases or in 500 Chinese controls. Functional studies of the variant were not performed.


.0007 DEAFNESS, X-LINKED 5

AIFM1, ARG422GLN
  
RCV000149865...

In 3 affected brothers from a Chinese family (family 2423) with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified a hemizygous c.1265G-A transition (c.1265G-A, NM_004208.3) in exon 12 of the AIFM1 gene, resulting in an arg422-to-gln (R422Q) substitution. The variant was not found in the Exome Sequencing Project or 1000 Genomes Project databases or in 500 Chinese controls. Functional studies of the variant were not performed.


.0008 SPONDYLOEPIMETAPHYSEAL DYSPLASIA, X-LINKED, WITH HYPOMYELINATING LEUKODYSTROPHY

AIFM1, ASP237GLY
  
RCV000856716

In 4 Polish brothers (family 2) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), Mierzewska et al. (2017) identified a hemizygous c.710A-G transition (c.710A-G, NM_001130847.3) in exon 7 of the AIFM1 gene, resulting in an asp237-to-gly (D237G) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing and linkage analysis, segregated with the disorder in the family. The unaffected mother was a heterozygous carrier. The same heterozygous D237G mutation was found in an obligate carrier female from an unrelated family (family 1) in which 3 deceased males had a similar disorder (Bieganski et al., 1999). The mutation was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of 1,343 individuals from the Polish population. Functional studies of the variant and studies of patient cells were not performed.

Miyake et al. (2017) identified a de novo hemizygous D237G mutation in a male patient (P4 from family 3, previously reported by Kimura-Ohba et al., 2013) with the disorder. The variant was found by exome sequencing and confirmed by Sanger sequencing. The patient died at age 20 years. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a splicing defect.


.0009 SPONDYLOEPIMETAPHYSEAL DYSPLASIA, X-LINKED, WITH HYPOMYELINATING LEUKODYSTROPHY

AIFM1, ASP240ASP
  
RCV000735220...

In 2 unrelated males (P1 in family 1 and P8 in family 5) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), Miyake et al. (2017) identified a de novo hemizygous c.720C-T transition (c.720C-T, NM_004208.3) in exon 7 of the AIFM1 gene, which was predicted to result in a synonymous asp240-to-asp (D240D) substitution. The variant, which was found by whole-genome sequencing and confirmed by Sanger sequencing, occurred de novo in patient 1 and was inherited from the unaffected mother in patient 8. The variant was not present in the dbSNP (build 147) or ExAC databases. In silico analysis predicted that the variant could result in a splicing defect, and analysis of patient-derived fibroblasts and transdifferentiated osteoblasts from patient 1 showed decreased AIFM1 mRNA and protein levels compared to controls.


.0010 SPONDYLOEPIMETAPHYSEAL DYSPLASIA, X-LINKED, WITH HYPOMYELINATING LEUKODYSTROPHY

AIFM1, GLN235HIS
  
RCV000856718

In 3 male members of a family (family 4) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), Miyake et al. (2017) identified a hemizygous c.705G-C transversion (c.705G-C, NM_004208.3) in exon 7 of the AIFM1 gene, resulting in a gln235-to-his (Q235H) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 147) database. There was 1 female carrier of the mutation in the ExAC database. In silico analysis predicted that the variant could result in a splicing defect, and analysis of patient-derived fibroblasts and transdifferentiated osteoblasts from 1 patient showed decreased AIFM1 mRNA and protein levels compared to controls.


.0011 SPONDYLOEPIMETAPHYSEAL DYSPLASIA, X-LINKED, WITH HYPOMYELINATING LEUKODYSTROPHY

AIFM1, IVS6AS, T-G, -44
  
RCV000856719

In 4 male members of a family (family 6) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), previously reported by Neubauer et al. (2006), Miyake et al. (2017) identified a hemizygous T-to-G transversion (c.697-44T-G, NM_004208.3) in intron 6 of the AIFM1 gene, predicted to result in a splicing defect. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 147) or ExAC databases. Analysis of patient-derived fibroblasts and transdifferentiated osteoblasts from 1 patient showed decreased AIFM1 mRNA and protein levels compared to controls.


.0012 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6

AIFM1, GLY308GLU
  
RCV000907842...

In 2 brothers with combined oxidative phosphorylation deficiency-6 (COXPD6; 300816), Berger et al. (2011) identified a hemizygous c.923G-A transition in exon 9 of the AIFM1 gene, resulting in a gly308-to-glu (G308E) substitution at a highly conserved residue in the NADH-binding motif. The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; the unaffected mother was a carrier. Functional studies of the variant and studies of patient cells were not performed.


.0013 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6

AIFM1, GLY338GLU
  
RCV000907852

In 2 male first cousins, born of Italian sisters, with combined oxidative phosphorylation deficiency-6 (COXPD6; 300816), Diodato et al. (2016) identified a hemizygous c.1013G-A transition (c.1013G-A, NM_004208.3) in the AIFM1 gene, resulting in a gly338-to-glu (G338E) substitution at a highly conserved residue. The mutation, which was found by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 142) or ExAC databases. Western blot analysis of patient cells showed decreased levels of the AIFM1 protein compared to controls.


.0014 CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 4, WITH CEREBELLAR ATAXIA

AIFM1, GLY262SER
  
RCV000907854

In a 39-year-old man with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; 310490), Ardissone et al. (2015) identified a hemizygous c.784G-A transition (c.784G-A, NM_004208) in the AIFM1 gene, resulting in a gly262-to-ser (G262S) substitution at a conserved residue. The mutation, which was found by sequencing of a panel of genes involved in mitochondrial disorders, was inherited from the unaffected mother. It was not found in the ExAC database. Western blot analysis of patient fibroblasts showed decreased amounts of the protein, suggesting instability.


.0015 CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 4, WITH CEREBELLAR ATAXIA

AIFM1, MET340THR
  
RCV000415225...

In a 17-year-old boy (patient 1) with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; 310490), Heimer et al. (2018) identified a c.1019T-C transition in the AIFM1 gene, resulting in a met340-to-thr (M340T) substitution at a highly conserved residue close to the NAD binding site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Sequencing Project, and ExAC databases, as well as in-house controls. Functional studies of the variant and studies of patient cells were not performed.

In 7 affected males from a multigenerational Irish family with CMTX4 with cerebellar ataxia, Bogdanova-Mihaylova et al. (2019) identified a hemizygous M340T mutation. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.


.0016 CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 4, WITH CEREBELLAR ATAXIA

AIFM1, THR141ILE
  
RCV000907858

In an 11-year-old boy (patient 2) with clinical features consistent with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; 310490), Heimer et al. (2018) identified a de novo hemizygous c.422C-T transition in the AIFM1 gene, resulting in a thr141-to-ile (T141I) substitution at a highly conserved residue close to the FAD binding site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Sequencing Project, and ExAC databases, as well as in-house controls. Functional studies of the variant and studies of patient cells were not performed.


.0017 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6

AIFM1, VAL243LEU
  
RCV000907860...

In an 11-year-old boy with a protracted course of combined oxidative phosphorylation deficiency-6 (COXPD6; 300816), Kettwig et al. (2015) identified a hemizygous c.727G-T transversion (c.727G-T, NM_004208.3) in exon 7 of the AIFM1 gene, resulting in a val243-to-leu (V243L) substitution at a highly conserved residue in the FAD-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was not found in the 1000 Genomes Project or Exome Sequencing Project. Western blot analysis of patient muscle showed reduced levels of the mutant protein, suggesting decreased stability.


REFERENCES

  1. Andrabi, S. A., Kim, N. S., Yu, S.-W., Wang, H., Koh, D. W., Sasaki, M., Klaus, J. A., Otsuka, T., Zhang, Z., Koehler, R. C., Hurn, P. D., Poirier, G. G., Dawson, V. L., Dawson, T. M. Poly(ADP-ribose) (PAR) polymer is a death signal. Proc. Nat. Acad. Sci. 103: 18308-18313, 2006. [PubMed: 17116882, images, related citations] [Full Text]

  2. Ardissone, A., Piscosquito, G., Legati, A., Langella, T., Lamantea, E., Garavaglia, B., Salsano, E., Farina, L., Moroni, I., Pareyson, D., Ghezzi, D. A slowly progressive mitochondrial encephalomyopathy widens the spectrum of AIFM1 disorders. Neurology 84: 2193-2195, 2015. [PubMed: 25934856, related citations] [Full Text]

  3. Berger, I., Ben-Neriah, Z., Dor-Wolman, T., Shaag, A., Saada, A., Zenvirt, S., Raas-Rothschild, A., Nadjari, M., Kaestner, K. H., Elpeleg, O. Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing. Molec. Genet. Metab. 104: 517-520, 2011. [PubMed: 22019070, related citations] [Full Text]

  4. Bieganski, T., Dawydzik, B., Kozlowski, K. Spondylo-epimetaphyseal dysplasia: a new X-linked variant with mental retardation. Europ. J. Pediat. 158: 809-814, 1999. [PubMed: 10486082, related citations] [Full Text]

  5. Bogdanova-Mihaylova, P., Alexander, M. D., Murphy, R. P., Chen, H., Healy, D. G., Walsh, R. A., Murphy, S. M. Clinical spectrum of AIFM1-associated disease in an Irish family, from mild neuropathy to severe cerebellar ataxia with colour blindness. J. Peripher. Nerv. Syst. 24: 348-353, 2019. [PubMed: 31523922, related citations] [Full Text]

  6. Brown, D., Yu, B. D., Joza, N., Benit, P., Meneses, J., Firpo, M., Rustin, P., Penninger, J. M., Martin, G. R. Loss of Aif function causes cell death in the mouse embryo, but the temporal progression of patterning is normal. Proc. Nat. Acad. Sci. 103: 9918-9923, 2006. [PubMed: 16788063, images, related citations] [Full Text]

  7. Cowchock, F. S., Duckett, S. W., Streletz, L. J., Graziani, L. J., Jackson, L. G. X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder. Am. J. Med. Genet. 20: 307-315, 1985. [PubMed: 3856385, related citations] [Full Text]

  8. Diodato, D., Tasca, G., Verrigni, D., D'Amico, A., Rizza, T., Tozzi, G., Martinelli, D., Verardo, M., Invernizzi, F., Nasca, A., Bellachio, E., Ghezzi, D., Piemonte, F., Dionisi-Vici, C., Carrozzo, R., Bertini, E. A novel AIFM1 mutation expands the phenotype to an infantile motor neuron disease. Europ. J. Hum. Genet. 24: 463-466, 2016. [PubMed: 26173962, related citations] [Full Text]

  9. Ghezzi, D., Sevrioukova, I., Invernizzi, F., Lamperti, C., Mora, M., D'Adamo, P., Novara, F., Zuffardi, O., Uziel, G., Zeviani, M. Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor. Am. J. Hum. Genet. 86: 639-649, 2010. [PubMed: 20362274, images, related citations] [Full Text]

  10. Gross, M. B. Personal Communication. Baltimore, Md. 1/30/2013.

  11. Heimer, G., Eyal, E., Zhu, X., Ruzzo, E. K., Marek-Yagel, D., Sagiv, D., Anikster, Y., Reznik-Wolf, H., Pras, E., Levi, D. O., Lancet, D., Ben-Zeev, B., Nissenkorn, A. Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin. Europ. J. Paediat. Neurol. 22: 93-101, 2018. [PubMed: 28967629, related citations] [Full Text]

  12. Joza, N., Pospisilik, J. A., Hangen, E., Hanada, T., Modjtahedi, N., Penninger, J. M., Kroemer, G. AIF: not just an apoptosis-inducing factor. Ann. N.Y. Acad. Sci. 1171: 2-11, 2009. [PubMed: 19723031, related citations] [Full Text]

  13. Joza, N., Susin, S. A., Daugas, E., Stanford, W. L., Cho, S. K., Li, C. Y. J., Sasaki, T., Elia, A. J., Cheng, H.-Y. M., Ravagnan, L., Ferri, K. F., Zamzami, N., Wakeham, A., Hakem, R., Yoshida, H., Kong, Y.-Y., Mak, T. W., Zuniga-Pflucker, J. C., Kroemer, G., Penninger, J. M. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 410: 549-554, 2001. [PubMed: 11279485, related citations] [Full Text]

  14. Kettwig, M., Schubach, M., Zimmermann, F. A., Klinge, L., Mayr, J. A., Biskup, S., Sperl, W., Gartner, J., Huppke, P. From ventriculomegaly to severe muscular atrophy: expansion of the clinical spectrum related to mutations in AIFM1. Mitochondrion 21: 12-18, 2015. [PubMed: 25583628, related citations] [Full Text]

  15. Kimura-Ohba, S., Kagitani-Shimono, K., Hashimoto, N., Nabatame, S., Okinaga, T., Murakami, A., Miyake, N., Matsumoto, N., Osaka, H., Hojo, K., Tomita, R., Taniike, M., Ozono, D. A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia. Am. J. Med. Genet. 161A: 203-207, 2013. [PubMed: 23239615, related citations] [Full Text]

  16. Klein, J. A., Longo-Guess, C. M., Rossmann, M. P., Seburn, K. L., Hurd, R. E., Frankel, W. N., Bronson, R. T., Ackerman, S. L. The harlequin mouse mutation down-regulates apoptosis-inducing factor. Nature 419: 367-374, 2002. [PubMed: 12353028, related citations] [Full Text]

  17. Mierzewska, H., Rydzanicz, M., Bieganski, T., Kosinska, J., Mierzewska-Schmidt, M., Lugowska, A., Pollak, A., Stawinski, P., Walczak, A., Kedra, A., Obersztyn, E., Ploski, R. Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation--a novel phenotype of the mitochondrial disease. Clin. Genet. 91: 30-37, 2017. [PubMed: 27102849, related citations] [Full Text]

  18. Miyake, N., Wolf, N. I., Cayami, F. K., Crawford, J., Bley, A., Bulas, D., Conant, A., Bent, S. J., Gripp, K. W., Hahn, A., Humphray, S., Kimura-Ohba, S., and 17 others. X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1. Neurogenetics 18: 185-194, 2017. [PubMed: 28842795, related citations] [Full Text]

  19. Neubauer, B. A., Stefanova, I., Hubner, C. A., Neumaier-Probst, E., Bohl. J., Oppermann, H. C., Stoss, H., Hahn, A., Stephani, U., Kohlschutter, A., Gal, A. A new type of leukoencephalopathy with metaphyseal chondrodysplasia maps to Xq25-q27. Neurology 67: 587-591, 2006. [PubMed: 16924009, related citations] [Full Text]

  20. Rinaldi, C., Grunseich, C., Sevrioukova, I. F., Schindler, A., Horkayne-Szakaly, I., Lamperti, C., Landoure, G., Kennerson, M. L., Burnett, B. G., Bonnemann, C., Biesecker, L. G., Ghezzi, D., Zeviani, M., Fischbeck, K. H. Cowchock syndrome is associated with a mutation in apoptosis-inducing factor. Am. J. Hum. Genet. 91: 1095-1102, 2012. [PubMed: 23217327, images, related citations] [Full Text]

  21. Sanges, D., Comitato, A., Tammaro, R., Marigo, V. Apoptosis in retinal degeneration involves cross-talk between apoptosis-inducing factor (AIF) and caspase-12 and is blocked by calpain inhibitors. Proc. Nat. Acad. Sci. 103: 17366-17371, 2006. [PubMed: 17088543, images, related citations] [Full Text]

  22. Susin, S. A., Lorenzo, H. K., Zamzami, N., Marzo, I., Snow, B. E., Brothers, G. M., Mangion, J., Jacotot, E., Constantini, P., Loeffler, M., Larochette, N., Goodlett, D. R., Aebersold, R., Siderovski, D. P., Penninger, J. M., Kroemer, G. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397: 441-446, 1999. [PubMed: 9989411, related citations] [Full Text]

  23. Wang, Q. J., Li, Q. Z., Rao, S. Q., Lee, K., Huang, X. S., Yang, W. Y., Zhai, S. Q., Guo, W. W., Guo, Y. F., Yu, N., Zhao, Y. L., Yuan, H., Guan, Y., Leal, S. M., Han, D. Y., Shen, Y. AUNX1, a novel locus responsible for X linked recessive auditory and peripheral neuropathy, maps to Xq23-27.3. (Letter) J. Med. Genet. 43: e33, 2006. Note: Electronic Article. [PubMed: 16816020, images, related citations] [Full Text]

  24. Wang, X., Yang, C., Chai, J., Shi, Y., Xue, D. Mechanisms of AIF-mediated apoptotic DNA degradation in Caenorhabditis elegans. Science 298: 1587-1592, 2002. [PubMed: 12446902, related citations] [Full Text]

  25. Yu, S.-W., Andrabi, S. A., Wang, H., Kim, N. S., Poirier, G. G., Dawson, T. M., Dawson, V. L. Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc. Nat. Acad. Sci. 103: 18314-18319, 2006. [PubMed: 17116881, images, related citations] [Full Text]

  26. Yu, S.-W., Wang, H., Poitras, M. F., Coombs, C., Bowers, W. J., Federoff, H. J., Poirier, G. G., Dawson, T. M., Dawson, V. L. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297: 259-263, 2002. [PubMed: 12114629, related citations] [Full Text]

  27. Zong, L., Guan, J., Ealy, M., Zhang, Q., Wang, D., Wang. H., Zhao, Y., Shen, Z., Campbell, C. A., Wang, F., Yang, J., Sun, W., and 18 others. Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder. J. Med. Genet. 52: 523-531, 2015. [PubMed: 25986071, images, related citations] [Full Text]


Cassandra L. Kniffin - updated : 11/26/2019
Cassandra L. Kniffin - updated : 11/25/2015
Matthew B. Gross - updated : 1/30/2013
Cassandra L. Kniffin - updated : 1/29/2013
Cassandra L. Kniffin - updated : 4/30/2010
Patricia A. Hartz - updated : 2/2/2007
Patricia A. Hartz - updated : 12/18/2006
Patricia A. Hartz - updated : 8/16/2006
Ada Hamosh - updated : 11/25/2002
Ada Hamosh - updated : 10/18/2002
Ada Hamosh - updated : 7/24/2002
Ada Hamosh - updated : 4/4/2001
Creation Date:
Ada Hamosh : 2/5/1999
carol : 01/24/2020
alopez : 12/10/2019
ckniffin : 12/09/2019
carol : 12/02/2019
carol : 11/27/2019
ckniffin : 11/26/2019
carol : 12/19/2016
alopez : 09/19/2016
carol : 11/25/2015
ckniffin : 11/25/2015
carol : 4/13/2015
mgross : 1/30/2013
carol : 1/30/2013
ckniffin : 1/29/2013
wwang : 5/4/2010
ckniffin : 4/30/2010
ckniffin : 4/30/2010
alopez : 7/21/2009
alopez : 2/2/2007
wwang : 12/20/2006
terry : 12/18/2006
mgross : 8/25/2006
terry : 8/16/2006
alopez : 12/3/2002
terry : 11/25/2002
alopez : 10/21/2002
terry : 10/18/2002
cwells : 7/29/2002
terry : 7/24/2002
alopez : 4/5/2001
terry : 4/4/2001
alopez : 6/4/1999
alopez : 2/5/1999

* 300169

APOPTOSIS-INDUCING FACTOR, MITOCHONDRIA-ASSOCIATED, 1; AIFM1


Alternative titles; symbols

APOPTOSIS-INDUCING FACTOR; AIF
PROGRAMMED CELL DEATH 8; PDCD8


HGNC Approved Gene Symbol: AIFM1

SNOMEDCT: 763400005;  


Cytogenetic location: Xq26.1     Genomic coordinates (GRCh38): X:130,129,362-130,165,841 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Xq26.1 Combined oxidative phosphorylation deficiency 6 300816 X-linked recessive 3
Cowchock syndrome 310490 X-linked recessive 3
Deafness, X-linked 5 300614 X-linked recessive 3
Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy 300232 X-linked recessive 3

TEXT

Description

The AIFM1 gene encodes a mitochondrial flavin adenine dinucleotide (FAD)-dependent oxidoreductase that plays a role in oxidative phosphorylation (OxPhos) and redox control in healthy cells. After mitochondrial outer membrane permeabilization, which is a feature of most, if not all, apoptotic pathways, AIFM1 is released from mitochondria and translocates to the nucleus, where it mediates nuclear features of apoptosis such as chromatin condensation and large-scale DNA degradation (summary by Joza et al., 2009).


Cloning and Expression

Susin et al. (1999) identified and cloned an apoptosis-inducing factor, AIF, that is sufficient to induce apoptosis of isolated nuclei. They cloned the mouse homolog of AIF, which has 92% amino acid identity to the human protein. The full-length proteins of both mouse and human contain 2 mitochondrial localization sequences and 2 putative nuclear localization signals. Mature mouse AIF has a molecular mass 57 kD that shares homology with the bacterial oxidoreductases, whereas the mouse precursor AIF transcript is 67 kD. AIF was normally confined to the mitochondrial intermembrane space, but translocated to the nucleus when apoptosis is induced. Recombinant AIF caused chromatin condensation and large scale fragmentation of DNA in isolated HeLa cell nuclei. It induced purified mitochondria to release the apoptogenic proteins cytochrome c (123970) and caspase-9 (602234). Microinjection of AIF into the cytoplasm of intact cells induced condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of the effects were prevented by pretreatment with a caspase inhibitor. Overexpression of BCL2 (151430), which controls the opening of mitochondrial permeability transition pores, prevented the release of AIF from the mitochondrion, but did not affect its apoptogenic activity. Susin et al. (1999) concluded that AIF is the principal mitochondrial factor causing nuclear apoptosis. They postulated that the caspases, DFF/CAD (601883), and AIF are engaged in complementary cooperative or redundant pathways that lead to nuclear apoptosis.

Ghezzi et al. (2010) identified human AIF as a 62-kD mature mitochondrion-specific protein that binds FAD and attaches by an N-terminal transmembrane domain to the inner mitochondrial membrane, where is functions as an NADH oxidase. Upon apoptogenic stimuli, the 57-kD soluble AIF containing 512 amino acids is released by proteolytic cleavage and translocates from the mitochondria to the nucleus, where it binds to chromosomal DNA and induces chromatin condensation and DNA fragmentation by attracting and activating a set of endonucleases. The full-length human precursor protein is a 67-kD polypeptide and contains 613 amino acids. After mitochondrial import, cleavage of a 54-amino acid mitochondrial targeting sequence results in the 62-kD mature protein containing 559 amino acids.

Zong et al. (2015) found ubiquitous expression of the Aifm1 gene in the mouse inner ear, especially in the cytoplasm of inner and outer hair cells and spiral ganglion neurons, consistent with a role in normal auditory function.


Mapping

By its inclusion within a mapped clone (GenBank Z81364), Susin et al. (1999) mapped the AIFM1 gene to chromosome Xq25-q26.

Gross (2013) mapped the AIFM1 gene to chromosome Xq26.1 based on an alignment of the AIFM1 sequence (GenBank AF100928) with the genomic sequence (GRCh37).


Gene Function

Programmed cell death is a fundamental requirement for embryogenesis, organ metamorphosis, and tissue homeostasis. In mammals, release of mitochondrial cytochrome c leads to cytosolic assembly of the apoptosome--a caspase activation complex involving APAF1 (602233) and caspase-9 that induces hallmarks of apoptosis. There are, however, mitochondrially regulated cell death pathways that are independent of APAF1/caspase-9. Like cytochrome c, AIF is localized to mitochondria and released in response to death stimuli. Joza et al. (2001) showed that genetic inactivation of AIF renders embryonic stem cells resistant to cell death after serum deprivation. Moreover, AIF is essential for programmed cell death during cavitation of embryoid bodies--the very first wave of cell death indispensable for mouse morphogenesis. AIF-dependent cell death displays structural features of apoptosis, and can be genetically uncoupled from APAF1 and caspase-9 expression. Joza et al. (2001) concluded that their data provide genetic evidence for a caspase-independent pathway of programmed cell death that controls early morphogenesis.

Yu et al. (2002) demonstrated that poly(ADP-ribose) polymerase-1 (PARP1; 173870) activation is required for translocation of AIF from the mitochondria to the nucleus and that AIF is necessary for PARP1-dependent cell death. N-methyl-N-prime-nitro-N-nitrosoguanidine, hydrogen peroxide, and NMDA induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP1-dependent cytotoxicity. Yu et al. (2002) concluded that their data support a model in which PARP1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death.

Andrabi et al. (2006) and Yu et al. (2006) demonstrated that the product of PARP1 activity, poly(ADP-ribose) (PAR) polymer, mediates PARP1-induced cell death. Yu et al. (2006) showed that PAR polymer induced the release of Aif from mitochondria in mouse cortical neurons and induced its translocation to nuclei. They also showed that poly(ADP-ribose) glycohydrolase (PARG; 603501) prevented Parp1-dependent Aif release. Furthermore, cells with reduced levels of Aif were resistant to PARP1-dependent cell death and PAR polymer cytotoxicity.

Joza et al. (2009) provided a review of AIFM1 functional and animal model studies and discussed its role in caspase-independent cell death pathways, mitochondrial metabolism and redox control, and obesity and diabetes.


Molecular Genetics

Combined Oxidative Phosphorylation Deficiency 6

In 2 Italian male first cousins, born of monozygotic twin sisters and unrelated fathers, with combined oxidative phosphorylation deficiency resulting in a severe mitochondrial encephalomyopathy (COXPD6; 300816), Ghezzi et al. (2010) identified a hemizygous deletion in the AIFM1 gene (300169.0001). Both had onset in the first year of life of psychomotor regression, muscle weakness and atrophy, lack of further development, and abnormal signals in the basal ganglia. One died at age 16 months, and the other was tetraplegic and wheelchair-bound with an inability to communicate at age 5 years. In vitro studies showed that the AIFM1 mutation resulted in destabilization of the inner mitochondrial membrane with subsequent damage to respiratory chain structure and activities. In addition, the mutation resulted in impaired control of mitochondrion-derived programmed cell death.

In 2 brothers with COXPD6, Berger et al. (2011) identified a hemizygous mutation in the AIFM1 gene (G308E; 300169.0012). The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; the unaffected mother was a carrier. Functional studies of the variant and studies of patient cells were not performed.

In 2 male first cousins, born of Italian sisters, with COXPD6, Diodato et al. (2016) identified a hemizygous missense mutation in the AIFM1 gene (G338E; 300169.0013). The mutation, which was found by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 142) or ExAC databases. Western blot analysis of patient cells showed decreased levels of the AIFM1 protein compared to controls.

Cowchock Syndrome/X-Linked Charcot-Marie-Tooth Disease 4 With or Without Cerebellar Ataxia

In affected members of the original family with Cowchock syndrome (310490), also known as X-linked recessive Charcot-Marie-Tooth disease-4 (CMTX4), reported by Cowchock et al. (1985), Rinaldi et al. (2012) identified a hemizygous mutation in the AIFM1 gene (E493V; 300169.0002). The mutation was identified by exome sequencing in 1 affected family member and confirmed by Sanger sequencing to segregate with the disorder within the family. Studies of the recombinant E493V mutant protein showed some structural changes that altered the redox properties of the protein without affecting activity of the respiratory chain complexes. Patient muscle biopsy showed an increased number of apoptotic cells compared to controls, suggesting activation of the caspase-independent cell death pathway. The phenotype was characterized by early-onset axonal sensorimotor neuropathy associated in some patients with hearing loss and cognitive impairment. The findings expanded the spectrum of disorders associated with AIFM1 mutations.

In a 39-year-old man with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; 310490), Ardissone et al. (2015) identified a hemizygous missense mutation in the AIFM1 gene (G262S; 300169.0014). The mutation, which was found by sequencing of a panel of genes involved in mitochondrial disorders, was inherited from the unaffected mother. Western blot analysis of patient fibroblasts showed decreased amounts of the protein, suggesting instability.

In 7 affected males from a multigenerational Irish family with CMTX4 with cerebellar ataxia, Bogdanova-Mihaylova et al. (2019) identified a hemizygous missense mutation in the AIFM1 gene (M340T; 300169.0015). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.

X-linked Deafness 5

In affected members of 5 unrelated Chinese families with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified 5 different missense mutations in the AIFM1 gene (300169.0003-300169.0007). Mutations in the first 2 families were found by whole-exome sequencing and confirmed by Sanger sequencing. Screening of this gene identified the same or additional hemizygous mutations in 11 (10%) of 93 men with sporadic auditory sensory disorder. The mutations segregated with the disorder in the families, and female carriers were unaffected. Of the 11 different missense variants identified, most occurred in the NADH and second FAD domains of the protein, which are essential for FAD-dependent NADH oxidoreductase. Functional studies of the variants were not performed.

X-linked Spondyloepimetaphyseal Dysplasia With Hypomyelinating Leukodystrophy

In 4 Polish brothers (family 2) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), Mierzewska et al. (2017) identified a hemizygous missense mutation in exon 7 of the AIFM1 gene (D237G; 300169.0008). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing and linkage analysis, segregated with the disorder in the family. The unaffected mother was a heterozygous carrier. The same heterozygous D237G mutation was found in an obligate carrier female from an unrelated family (family 1) in which 3 deceased males had a similar disorder (Bieganski et al., 1999). The mutation was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of 1,343 individuals from the Polish population. Functional studies of the variant and studies of patient cells were not performed.

In 12 affected males from 6 unrelated families with SEMDHL, Miyake et al. (2017) identified hemizygous mutations in the AIFM1 gene (see, e.g., 300169.0008-300169.0011). The variants, which were found by whole-genome or whole-exome sequencing, either occurred de novo or were inherited from unaffected mothers. All the mutations clustered around exon 7, suggesting a specific functional impairment, and in silico analysis predicted that the variants would result in splicing defects. Analysis of fibroblasts and transdifferentiated osteoblasts derived from some patients showed decreased AIFM1 mRNA and protein levels compared to controls. Miyake et al. (2017) concluded that AIFM1 plays a role in bone metabolism and myelination, which would account for the unique constellation of features in this disorder.


Animal Model

Harlequin (Hq) mutant mice have progressive degeneration of terminally differentiated cerebellar and retinal neurons. Klein et al. (2002) identified the Hq mutation as a proviral insertion in the Aif gene, causing an approximately 80% reduction in Aif expression. Mutant cerebellar granular cells were susceptible to exogenous and endogenous peroxide-mediated apoptosis, but could be rescued by Aif expression. Overexpression of Aif in wildtype granule cells further decreased peroxide-mediated cell death, suggesting that AIF serves as a free radical scavenger. In agreement, dying neurons in aged Hq mutant mice showed oxidative stress. In addition, neurons damaged by oxidative stress in both the cerebellum and retina of Hq mutant mice reentered the cell cycle before undergoing apoptosis. The results of Klein et al. (2002) provided a genetic model of oxidative stress-mediated neurodegeneration and demonstrated a direct connection between cell cycle reentry and oxidative stress in the aging central nervous system.

Wang et al. (2002) reported that inactivation of the C. elegans AIF homolog WAH-1 by RNA interference delayed the normal progression of apoptosis and caused a defect in apoptotic DNA degradation. WAH-1 localized in C. elegans mitochondria and was released into the cytosol and nucleus by the BH3-domain protein EGL1 (606266) in a caspase (CED3)-dependent manner. In addition, WAH-1 associated and cooperated with the mitochondrial endonuclease CPS6-endonuclease G (600440) to promote DNA degradation and apoptosis. Thus, AIF and EndoG define a single, mitochondria-initiated apoptotic DNA degradation pathway that is conserved between C. elegans and mammals.

Brown et al. (2006) found that inactivating Aif in the early mouse embryo had no effect on the apoptosis-dependent process of cavitation in embryoid bodies and apoptosis associated with embryonic neural tube closure, indicating that Aif function is not required for apoptotic cell death in early mouse embryos. By embryonic day 9, loss of Aif function caused abnormal cell death, presumably due to reduced mitochondrial respiratory chain complex-1 activity. Because of this cell death, Aif-null embryos failed to increase significantly in size after embryonic day 9. However, patterning continued on an essentially normal schedule, such that embryonic day-10 Aif-null embryos with only about 10% of the normal cell number had the same somite number as their wildtype littermates. Brown et al. (2006) concluded that pattern formation in the mouse can occur independent of embryo size and cell number.

In the rd1 mouse model of retinitis pigmentosa (see 180072) and an in vitro cellular model, Sanges et al. (2006) found that both Aif and caspase-12 (CASP12; 608633) translocated to the nucleus of dying photoreceptors. Only differentiated rd1 photoreceptors underwent apoptosis, and apoptosis was never observed in amacrine, bipolar, or horizontal retinal neurons. Translocation of both apoptotic factors required increased intracellular calcium, and calpain (see CAPN1; 114220) inhibitors interfered with Aif and Casp12 activation and rd1 photoreceptor apoptosis. Knockdown of Aif or Casp12 by interfering RNA showed that Aif played a major role in this apoptotic event and that Casp12 had a reinforcing effect.


ALLELIC VARIANTS 17 Selected Examples):

.0001   COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6

AIFM1, 3-BP DEL, 601AGA
SNP: rs387906500, ClinVar: RCV000012302

In 2 Italian male first-cousins, born of monozygotic twin sisters and unrelated fathers, with combined oxidative phosphorylation deficiency resulting in a severe mitochondrial encephalomyopathy (COXPD6; 300816), Ghezzi et al. (2010) identified a hemizygous 3-bp deletion (601delAGA) in the AIFM1 gene, resulting in the deletion of arg201. Both had onset in the first year of life of psychomotor regression, muscle weakness and atrophy, lack of further development, and abnormal signals in the basal ganglia. One died at age 16 months, and the other was tetraplegic and wheelchair-bound with an inability to communicate at age 5 years. In silico analysis indicated that arg201 residue is part of a hairpin that forms the FAD-binding pouch and confers conformational stability to the flavoprotein. Thus, deletion of arg201 probably perturbs the functional properties of both oxidized and reduced forms of AIF. In vitro studies showed that the lifetime of the FADH2-NAD complex formed by mutant mitochondrial AIF was shorter than that observed with wildtype. The mutant protein also had increased susceptibility to proteolytic cleavage, indicating that it is a structurally unstable variant. The mutant protein also showed higher DNA binding affinity and potential ability to cause DNA damage compared to wildtype. Approximately 75% of mutant cells versus 23% of control cells showed mitochondrial fragmentation under galactose treatment, suggesting that cells containing the mutant are more sensitive to apoptotic stimuli than control cells. Mitochondrial fragmentation was associated with impaired oxidative phosphorylation. Riboflavin treatment of cells with the mutant protein showed a recovery of the filamentous network and improvement in cell viability, which corresponded to some clinical improvement seen in 1 of the patients with the mutation. Overall, the studies showed that the AIFM1 mutation resulted in destabilization of the inner mitochondrial membrane with subsequent damage to respiratory chain structure and activities. In addition, the mutation resulted in impaired control of mitochondrion-derived programmed cell death.


.0002   COWCHOCK SYNDROME

AIFM1, GLU493VAL
SNP: rs281864468, ClinVar: RCV000032801

In affected members of the original family with Cowchock syndrome (310490) reported by Cowchock et al. (1985), Rinaldi et al. (2012) identified a hemizygous 1478A-T transversion in exon 14 of the AIFM1 gene, resulting in a glu493-to-val (E493V) substitution at a highly conserved residue. The mutation was identified by exome sequencing in 1 affected family member and confirmed by Sanger sequencing to segregate with the disorder within the family. The mutation was not found in 712 control individuals. Studies of the recombinant E493V mutant protein showed that it had a lower Km for NADH compared to wildtype, and was reduced by NADH 4-fold faster than wildtype. The charge-transfer complex had a shorter half-life than wildtype, but retained its ability to dimerize upon reduction with NADH. The mutant protein altered the redox state without affecting respiratory chain complex activity. Patient muscle biopsy showed an increased number of apoptotic cells compared to controls, suggesting activation of the caspase-independent cell death pathway. The phenotype was characterized by early-onset axonal sensorimotor neuropathy associated in some patients with hearing loss and cognitive impairment.


.0003   DEAFNESS, X-LINKED 5

AIFM1, ARG451GLN
SNP: rs863225431, ClinVar: RCV000202363, RCV002254916

In affected male members of a large Chinese family (family AUNX1) with X-linked deafness-5 (DFNX5; 300614), originally reported by Wang et al. (2006), Zong et al. (2015) identified a hemizygous c.1352G-A transition (c.1352G-A, NM_004208.3) in exon 13 of the AIFM1 gene, resulting in an arg451-to-gln (R451Q) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project or Exome Sequencing Project databases or in 500 Chinese controls. Functional studies of the variant were not performed.


.0004   DEAFNESS, X-LINKED 5

AIFM1, LEU344PHE ({dbSNP rs184474885})
SNP: rs184474885, gnomAD: rs184474885, ClinVar: RCV000149862, RCV000868580, RCV002051816

In 2 Chinese brothers (family 0223) with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified a hemizygous c.1030C-T transition (rs184474885) in exon 10 of the AIFM1 gene, resulting in a leu344-to-phe (L344F) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was annotated in the dbSNP (build 141) database at a very low frequency (0.0005), but was not found in 500 Chinese controls. Screening for AIFM1 mutations in 93 unrelated patients with sporadic auditory neuropathy revealed that 3 additional unrelated patients carried the L344F mutation. Functional studies of the variant were not performed.


.0005   DEAFNESS, X-LINKED 5

AIFM1, THR260ALA
SNP: rs863225432, ClinVar: RCV000202359

In affected male members of a large Chinese family (family 7170) with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified a hemizygous c.778A-G transition (c.778A-G, NM_004208.3) in exon 7 of the AIFM1 gene, resulting in a thr260-to-ala (T260A) substitution. The variant was not found in the Exome Sequencing Project or 1000 Genomes Project databases or in 500 Chinese controls. Functional studies of the variant were not performed.


.0006   DEAFNESS, X-LINKED 5

AIFM1, ARG422TRP
SNP: rs724160020, ClinVar: RCV000149864, RCV001383393, RCV001532712, RCV001814071, RCV003467208, RCV003895033

In 3 affected males from a Chinese family (family 2724) with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified a hemizygous c.1264C-T transition (c.1264C-T, NM_004208.3) in exon 12 of the AIFM1 gene, resulting in an arg422-to-trp (R422W) substitution. Two unrelated patients with sporadic disease were also found to carry the R422W mutation. The variant was not found in the Exome Sequencing Project or 1000 Genomes Project databases or in 500 Chinese controls. Functional studies of the variant were not performed.


.0007   DEAFNESS, X-LINKED 5

AIFM1, ARG422GLN
SNP: rs724160021, ClinVar: RCV000149865, RCV003467209, RCV003764900

In 3 affected brothers from a Chinese family (family 2423) with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified a hemizygous c.1265G-A transition (c.1265G-A, NM_004208.3) in exon 12 of the AIFM1 gene, resulting in an arg422-to-gln (R422Q) substitution. The variant was not found in the Exome Sequencing Project or 1000 Genomes Project databases or in 500 Chinese controls. Functional studies of the variant were not performed.


.0008   SPONDYLOEPIMETAPHYSEAL DYSPLASIA, X-LINKED, WITH HYPOMYELINATING LEUKODYSTROPHY

AIFM1, ASP237GLY
SNP: rs1202786652, ClinVar: RCV000856716

In 4 Polish brothers (family 2) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), Mierzewska et al. (2017) identified a hemizygous c.710A-G transition (c.710A-G, NM_001130847.3) in exon 7 of the AIFM1 gene, resulting in an asp237-to-gly (D237G) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing and linkage analysis, segregated with the disorder in the family. The unaffected mother was a heterozygous carrier. The same heterozygous D237G mutation was found in an obligate carrier female from an unrelated family (family 1) in which 3 deceased males had a similar disorder (Bieganski et al., 1999). The mutation was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of 1,343 individuals from the Polish population. Functional studies of the variant and studies of patient cells were not performed.

Miyake et al. (2017) identified a de novo hemizygous D237G mutation in a male patient (P4 from family 3, previously reported by Kimura-Ohba et al., 2013) with the disorder. The variant was found by exome sequencing and confirmed by Sanger sequencing. The patient died at age 20 years. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a splicing defect.


.0009   SPONDYLOEPIMETAPHYSEAL DYSPLASIA, X-LINKED, WITH HYPOMYELINATING LEUKODYSTROPHY

AIFM1, ASP240ASP
SNP: rs1569418673, ClinVar: RCV000735220, RCV000856717, RCV002370001

In 2 unrelated males (P1 in family 1 and P8 in family 5) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), Miyake et al. (2017) identified a de novo hemizygous c.720C-T transition (c.720C-T, NM_004208.3) in exon 7 of the AIFM1 gene, which was predicted to result in a synonymous asp240-to-asp (D240D) substitution. The variant, which was found by whole-genome sequencing and confirmed by Sanger sequencing, occurred de novo in patient 1 and was inherited from the unaffected mother in patient 8. The variant was not present in the dbSNP (build 147) or ExAC databases. In silico analysis predicted that the variant could result in a splicing defect, and analysis of patient-derived fibroblasts and transdifferentiated osteoblasts from patient 1 showed decreased AIFM1 mRNA and protein levels compared to controls.


.0010   SPONDYLOEPIMETAPHYSEAL DYSPLASIA, X-LINKED, WITH HYPOMYELINATING LEUKODYSTROPHY

AIFM1, GLN235HIS
SNP: rs377527583, gnomAD: rs377527583, ClinVar: RCV000856718

In 3 male members of a family (family 4) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), Miyake et al. (2017) identified a hemizygous c.705G-C transversion (c.705G-C, NM_004208.3) in exon 7 of the AIFM1 gene, resulting in a gln235-to-his (Q235H) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 147) database. There was 1 female carrier of the mutation in the ExAC database. In silico analysis predicted that the variant could result in a splicing defect, and analysis of patient-derived fibroblasts and transdifferentiated osteoblasts from 1 patient showed decreased AIFM1 mRNA and protein levels compared to controls.


.0011   SPONDYLOEPIMETAPHYSEAL DYSPLASIA, X-LINKED, WITH HYPOMYELINATING LEUKODYSTROPHY

AIFM1, IVS6AS, T-G, -44
SNP: rs1603225182, ClinVar: RCV000856719

In 4 male members of a family (family 6) with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL; 300232), previously reported by Neubauer et al. (2006), Miyake et al. (2017) identified a hemizygous T-to-G transversion (c.697-44T-G, NM_004208.3) in intron 6 of the AIFM1 gene, predicted to result in a splicing defect. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 147) or ExAC databases. Analysis of patient-derived fibroblasts and transdifferentiated osteoblasts from 1 patient showed decreased AIFM1 mRNA and protein levels compared to controls.


.0012   COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6

AIFM1, GLY308GLU
SNP: rs1603224226, ClinVar: RCV000907842, RCV003311910

In 2 brothers with combined oxidative phosphorylation deficiency-6 (COXPD6; 300816), Berger et al. (2011) identified a hemizygous c.923G-A transition in exon 9 of the AIFM1 gene, resulting in a gly308-to-glu (G308E) substitution at a highly conserved residue in the NADH-binding motif. The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; the unaffected mother was a carrier. Functional studies of the variant and studies of patient cells were not performed.


.0013   COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6

AIFM1, GLY338GLU
SNP: rs1603223152, ClinVar: RCV000907852

In 2 male first cousins, born of Italian sisters, with combined oxidative phosphorylation deficiency-6 (COXPD6; 300816), Diodato et al. (2016) identified a hemizygous c.1013G-A transition (c.1013G-A, NM_004208.3) in the AIFM1 gene, resulting in a gly338-to-glu (G338E) substitution at a highly conserved residue. The mutation, which was found by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 142) or ExAC databases. Western blot analysis of patient cells showed decreased levels of the AIFM1 protein compared to controls.


.0014   CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 4, WITH CEREBELLAR ATAXIA

AIFM1, GLY262SER
SNP: rs1603224817, ClinVar: RCV000907854

In a 39-year-old man with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; 310490), Ardissone et al. (2015) identified a hemizygous c.784G-A transition (c.784G-A, NM_004208) in the AIFM1 gene, resulting in a gly262-to-ser (G262S) substitution at a conserved residue. The mutation, which was found by sequencing of a panel of genes involved in mitochondrial disorders, was inherited from the unaffected mother. It was not found in the ExAC database. Western blot analysis of patient fibroblasts showed decreased amounts of the protein, suggesting instability.


.0015   CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 4, WITH CEREBELLAR ATAXIA

AIFM1, MET340THR
SNP: rs1057518895, ClinVar: RCV000415225, RCV000789722, RCV001311404, RCV001385157

In a 17-year-old boy (patient 1) with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; 310490), Heimer et al. (2018) identified a c.1019T-C transition in the AIFM1 gene, resulting in a met340-to-thr (M340T) substitution at a highly conserved residue close to the NAD binding site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Sequencing Project, and ExAC databases, as well as in-house controls. Functional studies of the variant and studies of patient cells were not performed.

In 7 affected males from a multigenerational Irish family with CMTX4 with cerebellar ataxia, Bogdanova-Mihaylova et al. (2019) identified a hemizygous M340T mutation. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.


.0016   CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 4, WITH CEREBELLAR ATAXIA

AIFM1, THR141ILE
SNP: rs1603227409, ClinVar: RCV000907858

In an 11-year-old boy (patient 2) with clinical features consistent with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; 310490), Heimer et al. (2018) identified a de novo hemizygous c.422C-T transition in the AIFM1 gene, resulting in a thr141-to-ile (T141I) substitution at a highly conserved residue close to the FAD binding site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Sequencing Project, and ExAC databases, as well as in-house controls. Functional studies of the variant and studies of patient cells were not performed.


.0017   COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6

AIFM1, VAL243LEU
SNP: rs1603225138, ClinVar: RCV000907860, RCV003311911

In an 11-year-old boy with a protracted course of combined oxidative phosphorylation deficiency-6 (COXPD6; 300816), Kettwig et al. (2015) identified a hemizygous c.727G-T transversion (c.727G-T, NM_004208.3) in exon 7 of the AIFM1 gene, resulting in a val243-to-leu (V243L) substitution at a highly conserved residue in the FAD-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was not found in the 1000 Genomes Project or Exome Sequencing Project. Western blot analysis of patient muscle showed reduced levels of the mutant protein, suggesting decreased stability.


REFERENCES

  1. Andrabi, S. A., Kim, N. S., Yu, S.-W., Wang, H., Koh, D. W., Sasaki, M., Klaus, J. A., Otsuka, T., Zhang, Z., Koehler, R. C., Hurn, P. D., Poirier, G. G., Dawson, V. L., Dawson, T. M. Poly(ADP-ribose) (PAR) polymer is a death signal. Proc. Nat. Acad. Sci. 103: 18308-18313, 2006. [PubMed: 17116882] [Full Text: https://doi.org/10.1073/pnas.0606526103]

  2. Ardissone, A., Piscosquito, G., Legati, A., Langella, T., Lamantea, E., Garavaglia, B., Salsano, E., Farina, L., Moroni, I., Pareyson, D., Ghezzi, D. A slowly progressive mitochondrial encephalomyopathy widens the spectrum of AIFM1 disorders. Neurology 84: 2193-2195, 2015. [PubMed: 25934856] [Full Text: https://doi.org/10.1212/WNL.0000000000001613]

  3. Berger, I., Ben-Neriah, Z., Dor-Wolman, T., Shaag, A., Saada, A., Zenvirt, S., Raas-Rothschild, A., Nadjari, M., Kaestner, K. H., Elpeleg, O. Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing. Molec. Genet. Metab. 104: 517-520, 2011. [PubMed: 22019070] [Full Text: https://doi.org/10.1016/j.ymgme.2011.09.020]

  4. Bieganski, T., Dawydzik, B., Kozlowski, K. Spondylo-epimetaphyseal dysplasia: a new X-linked variant with mental retardation. Europ. J. Pediat. 158: 809-814, 1999. [PubMed: 10486082] [Full Text: https://doi.org/10.1007/s004310051211]

  5. Bogdanova-Mihaylova, P., Alexander, M. D., Murphy, R. P., Chen, H., Healy, D. G., Walsh, R. A., Murphy, S. M. Clinical spectrum of AIFM1-associated disease in an Irish family, from mild neuropathy to severe cerebellar ataxia with colour blindness. J. Peripher. Nerv. Syst. 24: 348-353, 2019. [PubMed: 31523922] [Full Text: https://doi.org/10.1111/jns.12348]

  6. Brown, D., Yu, B. D., Joza, N., Benit, P., Meneses, J., Firpo, M., Rustin, P., Penninger, J. M., Martin, G. R. Loss of Aif function causes cell death in the mouse embryo, but the temporal progression of patterning is normal. Proc. Nat. Acad. Sci. 103: 9918-9923, 2006. [PubMed: 16788063] [Full Text: https://doi.org/10.1073/pnas.0603950103]

  7. Cowchock, F. S., Duckett, S. W., Streletz, L. J., Graziani, L. J., Jackson, L. G. X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder. Am. J. Med. Genet. 20: 307-315, 1985. [PubMed: 3856385] [Full Text: https://doi.org/10.1002/ajmg.1320200214]

  8. Diodato, D., Tasca, G., Verrigni, D., D'Amico, A., Rizza, T., Tozzi, G., Martinelli, D., Verardo, M., Invernizzi, F., Nasca, A., Bellachio, E., Ghezzi, D., Piemonte, F., Dionisi-Vici, C., Carrozzo, R., Bertini, E. A novel AIFM1 mutation expands the phenotype to an infantile motor neuron disease. Europ. J. Hum. Genet. 24: 463-466, 2016. [PubMed: 26173962] [Full Text: https://doi.org/10.1038/ejhg.2015.141]

  9. Ghezzi, D., Sevrioukova, I., Invernizzi, F., Lamperti, C., Mora, M., D'Adamo, P., Novara, F., Zuffardi, O., Uziel, G., Zeviani, M. Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor. Am. J. Hum. Genet. 86: 639-649, 2010. [PubMed: 20362274] [Full Text: https://doi.org/10.1016/j.ajhg.2010.03.002]

  10. Gross, M. B. Personal Communication. Baltimore, Md. 1/30/2013.

  11. Heimer, G., Eyal, E., Zhu, X., Ruzzo, E. K., Marek-Yagel, D., Sagiv, D., Anikster, Y., Reznik-Wolf, H., Pras, E., Levi, D. O., Lancet, D., Ben-Zeev, B., Nissenkorn, A. Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin. Europ. J. Paediat. Neurol. 22: 93-101, 2018. [PubMed: 28967629] [Full Text: https://doi.org/10.1016/j.ejpn.2017.09.004]

  12. Joza, N., Pospisilik, J. A., Hangen, E., Hanada, T., Modjtahedi, N., Penninger, J. M., Kroemer, G. AIF: not just an apoptosis-inducing factor. Ann. N.Y. Acad. Sci. 1171: 2-11, 2009. [PubMed: 19723031] [Full Text: https://doi.org/10.1111/j.1749-6632.2009.04681.x]

  13. Joza, N., Susin, S. A., Daugas, E., Stanford, W. L., Cho, S. K., Li, C. Y. J., Sasaki, T., Elia, A. J., Cheng, H.-Y. M., Ravagnan, L., Ferri, K. F., Zamzami, N., Wakeham, A., Hakem, R., Yoshida, H., Kong, Y.-Y., Mak, T. W., Zuniga-Pflucker, J. C., Kroemer, G., Penninger, J. M. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 410: 549-554, 2001. [PubMed: 11279485] [Full Text: https://doi.org/10.1038/35069004]

  14. Kettwig, M., Schubach, M., Zimmermann, F. A., Klinge, L., Mayr, J. A., Biskup, S., Sperl, W., Gartner, J., Huppke, P. From ventriculomegaly to severe muscular atrophy: expansion of the clinical spectrum related to mutations in AIFM1. Mitochondrion 21: 12-18, 2015. [PubMed: 25583628] [Full Text: https://doi.org/10.1016/j.mito.2015.01.001]

  15. Kimura-Ohba, S., Kagitani-Shimono, K., Hashimoto, N., Nabatame, S., Okinaga, T., Murakami, A., Miyake, N., Matsumoto, N., Osaka, H., Hojo, K., Tomita, R., Taniike, M., Ozono, D. A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia. Am. J. Med. Genet. 161A: 203-207, 2013. [PubMed: 23239615] [Full Text: https://doi.org/10.1002/ajmg.a.35686]

  16. Klein, J. A., Longo-Guess, C. M., Rossmann, M. P., Seburn, K. L., Hurd, R. E., Frankel, W. N., Bronson, R. T., Ackerman, S. L. The harlequin mouse mutation down-regulates apoptosis-inducing factor. Nature 419: 367-374, 2002. [PubMed: 12353028] [Full Text: https://doi.org/10.1038/nature01034]

  17. Mierzewska, H., Rydzanicz, M., Bieganski, T., Kosinska, J., Mierzewska-Schmidt, M., Lugowska, A., Pollak, A., Stawinski, P., Walczak, A., Kedra, A., Obersztyn, E., Ploski, R. Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation--a novel phenotype of the mitochondrial disease. Clin. Genet. 91: 30-37, 2017. [PubMed: 27102849] [Full Text: https://doi.org/10.1111/cge.12792]

  18. Miyake, N., Wolf, N. I., Cayami, F. K., Crawford, J., Bley, A., Bulas, D., Conant, A., Bent, S. J., Gripp, K. W., Hahn, A., Humphray, S., Kimura-Ohba, S., and 17 others. X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1. Neurogenetics 18: 185-194, 2017. [PubMed: 28842795] [Full Text: https://doi.org/10.1007/s10048-017-0520-x]

  19. Neubauer, B. A., Stefanova, I., Hubner, C. A., Neumaier-Probst, E., Bohl. J., Oppermann, H. C., Stoss, H., Hahn, A., Stephani, U., Kohlschutter, A., Gal, A. A new type of leukoencephalopathy with metaphyseal chondrodysplasia maps to Xq25-q27. Neurology 67: 587-591, 2006. [PubMed: 16924009] [Full Text: https://doi.org/10.1212/01.wnl.0000230133.11951.75]

  20. Rinaldi, C., Grunseich, C., Sevrioukova, I. F., Schindler, A., Horkayne-Szakaly, I., Lamperti, C., Landoure, G., Kennerson, M. L., Burnett, B. G., Bonnemann, C., Biesecker, L. G., Ghezzi, D., Zeviani, M., Fischbeck, K. H. Cowchock syndrome is associated with a mutation in apoptosis-inducing factor. Am. J. Hum. Genet. 91: 1095-1102, 2012. [PubMed: 23217327] [Full Text: https://doi.org/10.1016/j.ajhg.2012.10.008]

  21. Sanges, D., Comitato, A., Tammaro, R., Marigo, V. Apoptosis in retinal degeneration involves cross-talk between apoptosis-inducing factor (AIF) and caspase-12 and is blocked by calpain inhibitors. Proc. Nat. Acad. Sci. 103: 17366-17371, 2006. [PubMed: 17088543] [Full Text: https://doi.org/10.1073/pnas.0606276103]

  22. Susin, S. A., Lorenzo, H. K., Zamzami, N., Marzo, I., Snow, B. E., Brothers, G. M., Mangion, J., Jacotot, E., Constantini, P., Loeffler, M., Larochette, N., Goodlett, D. R., Aebersold, R., Siderovski, D. P., Penninger, J. M., Kroemer, G. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397: 441-446, 1999. [PubMed: 9989411] [Full Text: https://doi.org/10.1038/17135]

  23. Wang, Q. J., Li, Q. Z., Rao, S. Q., Lee, K., Huang, X. S., Yang, W. Y., Zhai, S. Q., Guo, W. W., Guo, Y. F., Yu, N., Zhao, Y. L., Yuan, H., Guan, Y., Leal, S. M., Han, D. Y., Shen, Y. AUNX1, a novel locus responsible for X linked recessive auditory and peripheral neuropathy, maps to Xq23-27.3. (Letter) J. Med. Genet. 43: e33, 2006. Note: Electronic Article. [PubMed: 16816020] [Full Text: https://doi.org/10.1136/jmg.2005.037929]

  24. Wang, X., Yang, C., Chai, J., Shi, Y., Xue, D. Mechanisms of AIF-mediated apoptotic DNA degradation in Caenorhabditis elegans. Science 298: 1587-1592, 2002. [PubMed: 12446902] [Full Text: https://doi.org/10.1126/science.1076194]

  25. Yu, S.-W., Andrabi, S. A., Wang, H., Kim, N. S., Poirier, G. G., Dawson, T. M., Dawson, V. L. Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc. Nat. Acad. Sci. 103: 18314-18319, 2006. [PubMed: 17116881] [Full Text: https://doi.org/10.1073/pnas.0606528103]

  26. Yu, S.-W., Wang, H., Poitras, M. F., Coombs, C., Bowers, W. J., Federoff, H. J., Poirier, G. G., Dawson, T. M., Dawson, V. L. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297: 259-263, 2002. [PubMed: 12114629] [Full Text: https://doi.org/10.1126/science.1072221]

  27. Zong, L., Guan, J., Ealy, M., Zhang, Q., Wang, D., Wang. H., Zhao, Y., Shen, Z., Campbell, C. A., Wang, F., Yang, J., Sun, W., and 18 others. Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder. J. Med. Genet. 52: 523-531, 2015. [PubMed: 25986071] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102961]


Contributors:
Cassandra L. Kniffin - updated : 11/26/2019
Cassandra L. Kniffin - updated : 11/25/2015
Matthew B. Gross - updated : 1/30/2013
Cassandra L. Kniffin - updated : 1/29/2013
Cassandra L. Kniffin - updated : 4/30/2010
Patricia A. Hartz - updated : 2/2/2007
Patricia A. Hartz - updated : 12/18/2006
Patricia A. Hartz - updated : 8/16/2006
Ada Hamosh - updated : 11/25/2002
Ada Hamosh - updated : 10/18/2002
Ada Hamosh - updated : 7/24/2002
Ada Hamosh - updated : 4/4/2001

Creation Date:
Ada Hamosh : 2/5/1999

Edit History:
carol : 01/24/2020
alopez : 12/10/2019
ckniffin : 12/09/2019
carol : 12/02/2019
carol : 11/27/2019
ckniffin : 11/26/2019
carol : 12/19/2016
alopez : 09/19/2016
carol : 11/25/2015
ckniffin : 11/25/2015
carol : 4/13/2015
mgross : 1/30/2013
carol : 1/30/2013
ckniffin : 1/29/2013
wwang : 5/4/2010
ckniffin : 4/30/2010
ckniffin : 4/30/2010
alopez : 7/21/2009
alopez : 2/2/2007
wwang : 12/20/2006
terry : 12/18/2006
mgross : 8/25/2006
terry : 8/16/2006
alopez : 12/3/2002
terry : 11/25/2002
alopez : 10/21/2002
terry : 10/18/2002
cwells : 7/29/2002
terry : 7/24/2002
alopez : 4/5/2001
terry : 4/4/2001
alopez : 6/4/1999
alopez : 2/5/1999