Alternative titles; symbols
HGNC Approved Gene Symbol: TIMM8A
SNOMEDCT: 702423009;
Cytogenetic location: Xq22.1 Genomic coordinates (GRCh38): X:101,345,661-101,348,742 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq22.1 | Mohr-Tranebjaerg syndrome | 304700 | X-linked recessive | 3 |
TIMM8A belongs to a family of evolutionary conserved proteins that are organized in heterooligomeric complexes in the mitochondrial intermembrane space. These proteins mediate the import and insertion of hydrophobic membrane proteins into the mitochondrial inner membrane.
Using information from a patient with a 21-kb deletion in Xq22 and sensorineural deafness along with dystonia (Mohr-Tranebjaerg syndrome; MTS; 304700), Jin et al. (1996) characterized a novel transcript lying within the deletion region. This gene, which they named DDP (deafness/dystonia peptide), showed high levels of expression in fetal and adult brain. The DDP protein demonstrated striking similarity to a predicted S. pombe protein of no known function. Thus, it is likely that the DDP gene encodes an evolutionarily conserved novel polypeptide necessary for normal human neurologic development.
Vetrie et al. (1993) had described a patient with a deletion of the BTK gene (300300) that extended into a second gene, designated DXS1274E, lying 3-prime of BTK. This was the gene that was subsequently renamed DDP by Jin et al. (1996). The deduced DDP protein contains 97 amino acids and has a molecular mass of about 11 kD. DDP shows ubiquitous expression,with highest levels in fetal and adult brain.
The DDP gene contains 2 exons and an intron of approximately 2 kb (Vetrie et al., 1993). The coding region spans both exons. The first exon of the cDNA sequence begins 770 bp downstream from the polyadenylation signal of BTK.
Koehler et al. (1999) identified the function of the DDP gene. They demonstrated that DDP has similarity to 5 small mitochondrial proteins (Tim8p, Tim9p, Tim10p, Tim12p, and Tim13p) of the yeast mitochondrial intermembrane space. Tim9p, Tim10p, and Tim12p mediate the import of metabolite transporters from the cytoplasm into the mitochondrial inner membrane and interact structurally and functionally with Tim8p and Tim13p. DDP was found to be most similar to Tim8p. Tim8p exists as a soluble 70-kD complex with Tim13p and Tim9p, and deletion of Tim8p is synthetically lethal with a conditional mutation in Tim10p. Koehler et al. (1999) concluded that the Mohr-Tranebjaerg syndrome is a novel type of mitochondrial disease that is most likely caused by a defective mitochondrial protein-import system.
Roesch et al. (2002) showed that DDP1 assembles in a 70-kD complex in the intermembrane space with TIMM13 (607383). DDP1 was not detectable in fibroblasts derived from a Mohr-Tranebjaerg syndrome patient with the cys66-to-trp mutation (C66W; 300356.0004) in the twin CX3C motif of DDP1, in which 2 cysteine residues are separated by 3 amino acids. The corresponding mutation in yeast Tim8p yielded an unstable protein that did not assemble with yeast Tim13p. DDP1 restored Tim23p import when expressed with TIMM13 in yeast mitochondria lacking the Tim8p-Tim13p complex, and DDP1 and TIMM13 could be crosslinked to the human TIMM23 (605034) import intermediate in rat and yeast mitochondria. In a similar manner to Tim8p, DDP1 mediated the import of human TIMM23. The authors hypothesized that MTS may be caused by decreased levels of TIMM23 in the mitochondrial inner membrane in affected tissues.
Roesch et al. (2004) determined that citrin (SLC25A13; 603859) and aralar (SLC25A12; 603667), which are Ca(2+)-binding aspartate/glutamate carriers (AGC) of the mitochondrial inner membrane, are substrates for the TIMM8A/TIMM13 complex.. The AGCs function in the aspartate-malate NADH shuttle that moves reducing equivalents from the cytosol to the mitochondrial matrix. A lymphoblast cell line derived from an MTS patient had decreased NADH levels and defects in mitochondrial protein import. Protein expression studies indicated that DDP1 and TIMM13 showed nonuniform expression in mammals, and expression was prominent in the large neurons in the brain, which is in agreement with the expression pattern of SLC25A12. Roesch et al. (2004) hypothesized that insufficient NADH shuttling, linked with changes in Ca(2+) concentration, in sensitive cells of the CNS might contribute to the pathologic process associated with MTS.
Mohr-Tranebjaerg Syndrome
In the original Norwegian family with Mohr-Tranebjaerg syndrome (MTS; 304700) reported by Mohr and Mageroy (1960) and studied by Tranebjaerg et al. (1995), Jin et al. (1996) demonstrated that affected males carried a 1-bp deletion in exon 1 of the DDP gene (151delT; 300356.0001).
Tranebjaerg et al. (2000) reported the first de novo mutation in the DDP gene in an 11-year-old Dutch boy with deafness and dystonia. Previously reported mutations had all been frameshifts/nonsense mutations or deletion of the entire gene as part of a larger deletion encompassing also the BTK gene. In this case, a missense mutation (C66W) caused an equally severe clinical picture.
Tranebjaerg et al. (1997) demonstrated a nonsense mutation (E24X; 300356.0003) in the DDP gene in a male who was originally thought to have a distinct disorder called Jensen syndrome. The patient's nephew was found to have the same nonsense mutation and the disorder was considered the same as MTS (Tranebjaerg et al., 2001).
Hofmann et al. (2002) transfected human TIMM8A carrying the C66W mutation into yeast cells and determined that the mutation did not effect expression of TIMM8A within the mitochondrial intermembrane space. The mutation did, however, produce an inactive protein that could not support mitochondrial import of proteins when coexpressed with its partner, TIMM13. Using binding, cross-linking, and biochemical studies of in vitro translated and recombinant human TIMM8A, Hofmann et al. (2002) found that the C66W mutation impaired the binding of Zn(2+) via the cys(4) zinc-binding motif. As a consequence, the mutated protein was incorrectly folded and lost its ability to assemble into heterohexameric 70-kD complexes with TIMM13. The mutant protein was also destabilized and was susceptible to enhanced proteolytic degradation.
In the original Norwegian family with Mohr-Tranebjaerg syndrome (MTS; 304700), Jin et al. (1996) demonstrated that affected males carried a 1-bp deletion in exon 1 (151delT). The consequent frameshift resulted in the incorporation of 25 novel amino acids after the glutamic acid at codon 38, followed by polypeptide termination.
In pedigree K8190 segregating for sensorineural deafness and dystonia (MTS; 304700) and the symptom of mental deficiency, Jin et al. (1996) found a 10-bp deletion in exon 2 of the DDP gene. This mutation created a frameshift that resulted in the addition of 12 novel amino acids after the methionine residue at codon 48, followed by polypeptide termination.
In a patient with Mohr-Tranebjaerg syndrome (MTS; 304700) from the original Dutch family thought to have a distinct disorder called Jensen syndrome, Tranebjaerg et al. (1997) identified a G-to-T transversion in exon 1 of the TIMM8A gene, resulting in a glu24-to-ter (E24X) substitution. Tranebjaerg et al. (2001) identified the same mutation in the patient's 21-year-old nephew.
Tranebjaerg et al. (2000) identified a de novo mutation in the DDP gene in an 11-year-old Dutch boy with deafness and dystonia (MTS; 304700). Whereas previously reported mutations had all been frameshifts/nonsense mutations or deletion of the entire gene, this was a missense mutation, cys66 to trp (C66W). This mutation caused an equally severe clinical picture. Sensorineural hearing impairment had been diagnosed at the age of 2.5 years; mild mental retardation and normal behavior were present. He was toilet-trained during the daytime by age 4. Although at the age of 3 years neurologic examination was normal, at ages 5 to 6 years he had lost skills such as drawing, playing with puppets, and similar tasks. From age 10, he had abnormal posture and trembling of the left hand, and increasing difficulties with tying his shoelaces and his belt.
In a family with Mohr-Tranebjaerg syndrome (MTS; 304700), Swerdlow and Wooten (2001) found that affected members had deletion of guanine-108 of the TIMM8A gene, which terminated the 97-amino acid protein at codon 25. Unlike previously reported kindreds, carrier females in this family also manifested dystonias, including torticollis and writer's cramp. At 28 years, the proband developed progressively worsening involuntary head and neck movements. Generalized dystonia and a markedly hypertrophied right sternocleidomastoid were present. Intermittent, involuntary contractions of the right sternocleidomastoid flexed his right ear onto his shoulder. Muscle tone was normal between paroxysms of dystonic contractions. The proband's mother had head shaking, chronic muscle pain, and writer's cramp beginning at age 25 years. The sister of the proband had onset of head shaking in her late teens and writer's cramp in her mid-twenties.
In a patient with sensorineural deafness and dystonia (MTS; 304700), Jin et al. (1996) found a 21-kb deletion in Xq22, resulting in deletion of the entire TIMM8A gene. The patient also suffered from X-linked agammaglobulinemia, caused by mutation in the neighboring BTK gene (300300).
Pizzuti et al. (2004) reported a 24-year-old man diagnosed at age 2 years with Bruton agammaglobulinemia and bilateral hearing loss. He later developed progressive visual loss at age 15 and progressive writing difficulties due to focal dystonia at age 19. The mild clinical features were unique in that the dystonia appeared late in life and was task specific, and he had only mild cognitive impairment. Molecular analysis detected complete deletion of the DDP1 gene and partial deletion of the BTK gene. Pizzuti et al. (2004) suggested that complete absence of the DDP1 protein may result in less significant effects on the mitochondrial multiprotein complex than truncated DDP1 peptides, which may disrupt the multiprotein complex and cause more severe clinical manifestations.
In affected members of a Japanese family with Mohr-Tranebjaerg syndrome (MTS; 304700), Ujike et al. (2001) identified a nonsense mutation, arg80-to-ter, in the TIMM8A gene, resulting in a truncated protein of 79 amino acids. The authors noted that this truncated protein is longer than that reported in other mutations and postulated that the longer amino acid sequence could be related to the milder clinical symptoms and slower progression in this Japanese family.
In 2 affected members of a Spanish family with Mohr-Tranebjaerg syndrome (MTS; 304700), Ezquerra et al. (2005) identified an A-to-C transversion at position -23 in intron 1 of the TIMM8A gene, referenced to the first nucleotide of exon 2 (IVS1-23A-C). The mutation is predicted to result in a splicing defect. One of the patients had onset at age 4 years, complete hearing loss, severe generalized dystonia, and loss of vision, whereas the other patient had onset at 11 years, mild hearing loss, mild focal dystonia, and behavioral disturbances. The patients' mothers and aunt were heterozygous for the mutation. The mutation was not identified in 90 control individuals.
In 2 Spanish brothers with Mohr-Tranebjaerg syndrome (MTS; 304700), Aguirre et al. (2006) identified a 1-bp deletion (127delT) in the TIMM8A gene, resulting in a frameshift and premature stop codon at residue 64. Their unaffected mother was heterozygous for the mutation.
Aguirre, L. A., del Castillo, I., Macaya, A., Meda, C., Villamar, M., Moreno-Pelayo, M. A., Moreno, F. A novel mutation in the gene encoding TIMM8a, a component of the mitochondrial protein translocase complexes, in a Spanish familial case of deafness-dystonia (Mohr-Tranebjaerg) syndrome. Am. J. Med. Genet. 140A: 392-397, 2006. [PubMed: 16411215] [Full Text: https://doi.org/10.1002/ajmg.a.31079]
Ezquerra, M., Campdelacreu, J., Munoz, E., Tolosa, E., Marti, M. J. A novel intronic mutation in the DDP1 gene in a family with X-linked dystonia-deafness syndrome. Arch. Neurol. 62: 306-308, 2005. [PubMed: 15710860] [Full Text: https://doi.org/10.1001/archneur.62.2.306]
Hofmann, S., Rothbauer, U., Muhlenbein, N., Neupert, W., Gerbitz, K.-D., Brunner, M., Bauer, M. F. The C66W mutation in the deafness dystonia peptide 1 (DDP1) affects the formation of functional DDP1-TIM13 complexes in the mitochondrial intermembrane space. J. Biol. Chem. 277: 23287-23293, 2002. [PubMed: 11956200] [Full Text: https://doi.org/10.1074/jbc.M201154200]
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Roesch, K., Curran, S. P., Tranebjaerg, L., Koehler, C. M. Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex. Hum. Molec. Genet. 11: 477-486, 2002. [PubMed: 11875042] [Full Text: https://doi.org/10.1093/hmg/11.5.477]
Roesch, K., Hynds, P. J., Varga, R., Tranebjaerg, L., Koehler, C. M. The calcium-binding aspartate/glutamate carriers, citrin and aralar1, are new substrates for the DDP1/TIMM8a-TIMM13 complex. Hum. Molec. Genet. 13: 2101-2111, 2004. [PubMed: 15254020] [Full Text: https://doi.org/10.1093/hmg/ddh217]
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Tranebjaerg, L., Hamel, B. C. J., Gabreels, F. J. M., Renier, W. O., Van Ghelue, M. A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness-dystonia-optic atrophy syndrome. Europ. J. Hum. Genet. 8: 464-467, 2000. [PubMed: 10878669] [Full Text: https://doi.org/10.1038/sj.ejhg.5200483]
Tranebjaerg, L., Jensen, P. K. A., Van Ghelue, M., Vnencak-Jones, C. L., Sund, S., Elgjo, K., Jakobsen, J., Lindal, S., Warburg, M., Fuglsang-Frederiksen, A., Skullerud, K. Neuronal cell death in the visual cortex is a prominent feature of the X-linked recessive mitochondrial deafness-dystonia syndrome caused by mutations in the TIMM8a gene. Ophthalmic Genet. 22: 207-223, 2001. [PubMed: 11803487] [Full Text: https://doi.org/10.1076/opge.22.4.207.2220]
Tranebjaerg, L., Schwartz, C., Eriksen, H., Andreasson, S., Ponjavic, V., Dahl, A., Stevenson, R. E., May, M., Arena, F., Barker, D., Elverland, H. H., Lubs, H. A new X linked recessive deafness syndrome with blindness, dystonia, fractures, and mental deficiency is linked to Xq22. J. Med. Genet. 32: 257-263, 1995. [PubMed: 7643352] [Full Text: https://doi.org/10.1136/jmg.32.4.257]
Tranebjaerg, L., van Ghelue, M., Nilssen, O., Hodes, M. E., Dlouhy, S. R., Farlow, M. R., Hamel, B., Arts, W. F. M., Jankovic, J., Beach, J., Jensen, P. K. A. Jensen syndrome is allelic to Mohr-Tranebjaerg syndrome and both are caused by stop mutations in the DDP gene. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A349 only, 1997.
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