Alternative titles; symbols
HGNC Approved Gene Symbol: ATG7
Cytogenetic location: 3p25.3 Genomic coordinates (GRCh38): 3:11,272,397-11,576,353 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p25.3 | Spinocerebellar ataxia, autosomal recessive 31 | 619422 | Autosomal recessive | 3 |
Autophagy is a process of bulk degradation of cytoplasmic components by the lysosomal/vacuolar system. ATG7 is a ubiquitin-activating enzyme E1 (see 314370)-like protein essential for the Apg12 (ATG12; 609608) conjugation system that mediates membrane fusion in autophagy (Tanida et al., 2001).
Yuan et al. (1999) identified several APG7L ESTs by searching a database for sequences similar to P. pastoris Apg7, and they sequenced an APG7L cDNA from an infant brain cDNA library. The deduced 703-amino acid protein contains a central putative E1-like ATP-binding site (GxGxxG), conserved charged amino acids flanking the GxGxxG motif, and a putative E1 active site with a conserved catalytic cysteine. APG7L shares similarity with the E1 enzymes UBA2 and UBA3 (UBE1C; 603172), and it shares 38% identity with yeast Apg7. EST database analysis indicated that APG7L is expressed by many diverse tissues.
Tanida et al. (2001) found that APG7L expressed by transfected human embryonic kidney cells had an apparent molecular mass of about 80 kD.
Gross (2012) mapped the ATG7 gene to chromosome 3p25.3 based on an alignment of the ATG7 sequence (GenBank BC000091) with the genomic sequence (GRCh37).
Using yeast 2-hybrid analysis, Tanida et al. (2001) found that APG7L interacts with APG12L. Site-directed mutagenesis revealed that cys572 of APG7L is an active site cysteine essential for formation of the APG7L-APG12L intermediate. Overexpression of APG7L enhanced the formation of the APG5L (ATG5; 604261)-APG12L conjugate, indicating that APG7L is an E1-like enzyme essential for the APG12 conjugation system. Cross-linking experiments and glycerol-gradient centrifugation analysis showed that APG7L forms homodimers. Coimmunoprecipitation studies indicated that 3 human Apg8 counterparts, GATE16 (GABARAPL2; 607452), GABARAP (605125), and MAP1ALC3 (601242), also form conjugates with APG7L. Like E1 enzymes, APG7L carrying a mutation of the active site cysteine (cys572 to ser) formed a stable intermediate via an O-ester bond instead of a thioester bond.
Tanida et al. (2002) found that ATG7 coimmunoprecipitated with ATG3 (609606), indicating that ATG3 forms an E1-E2 complex with ATG7, similar to the yeast Apg3-Apg7 complex.
Yu et al. (2004) defined a novel molecular pathway in which activation of the receptor-interacting protein (RIP; 603453), a serine-threonine kinase, and Jun amino-terminal kinase (JNK1; 601158) induced cell death with the morphology of autophagy. Autophagic death required the genes ATG7 (GSA7) and beclin-1 (604378) and was induced by caspase-8 (601763) inhibition. Yu et al. (2004) cautioned that clinical therapies involving caspase inhibitors may arrest apoptosis but also have the unanticipated effect of promoting autophagic cell death.
Sanjuan et al. (2007) demonstrated that a particle that engages Toll-like receptors on a murine macrophage while it is phagocytosed triggers the autophagosome marker LC3 (601242) to be rapidly recruited to the phagosome in a manner that depends on the autophagy pathway proteins ATG5 and ATG7; this process is preceded by recruitment of beclin-1 and phosphoinositide-3-OH kinase activity. Translocation of beclin-1 and LC3 to the phagosome was not associated with observable double-membrane structures characteristic of conventional autophagosomes, but was associated with phagosome fusion with lysosomes, leading to rapid acidification and enhanced killing of the ingested organism.
Nishida et al. (2009) showed that mouse cells lacking Atg5 or Atg7 can still form autophagosomes/autolysosomes and perform autophagy-mediated protein degradation when subjected to certain stressors. Lipidation of LC3 to form LC3-II, generally considered to be a good indicator of macroautophagy, did not occur during the Atg5/Atg7-independent alternative process of macroautophagy. Nishida et al. (2009) also found that this alternative process of macroautophagy was regulated by several autophagic proteins, including Unc51-like kinase-1 (ULK1; 603168) and beclin-1. Unlike conventional macroautophagy, autophagosomes seemed to be generated in a Rab9 (300284)-dependent manner by the fusion of isolation membranes with vesicles derived from the trans-Golgi and late endosomes. In vivo, Atg5-independent alternative macroautophagy was detected in several embryonic tissues. It also had a function in clearing mitochondria during erythroid maturation. Nishida et al. (2009) concluded that their results indicate that mammalian macroautophagy can occur through at least 2 different pathways: an Atg5/Atg7-dependent conventional pathway and an Atg5/Atg7-independent alternative pathway.
Lee et al. (2012) found that starved mouse embryonic fibroblasts lacking the essential autophagy gene product Atg7 failed to undergo cell cycle arrest. Independent of its E1-like enzymatic activity, Atg7 could bind to the tumor suppressor p53 (191170) to regulate the transcription of the gene encoding the cell cycle inhibitor p21(CDKN1A) (116899). With prolonged metabolic stress, the absence of Atg7 resulted in augmented DNA damage with increased p53-dependent apoptosis. Inhibition of the DNA damage response by deletion of the protein kinase Chk2 (604373) partially rescued postnatal lethality in Atg7 -/- mice. Thus, Lee et al. (2012) concluded that when nutrients are limited, Atg7 regulates p53-dependent cell cycle and cell death pathways.
Cinque et al. (2015) investigated the role of autophagy during bone growth, which is mediated by chondrocyte rate of proliferation, hypertrophic differentiation, and extracellular matrix (ECM) deposition in growth plates. They showed that autophagy is induced in growth plate chondrocytes during postnatal development and regulates the secretion of type II collagen (Col2; see 120140), the major component of cartilage ECM. Mice lacking Atg7 in chondrocytes experience endoplasmic reticulum storage of type II procollagen and defective formation of the Col2 fibrillary network in the ECM. Surprisingly, postnatal induction of chondrocyte autophagy is mediated by the growth factor FGF18 (603726) through FGFR4 (134935) and JNK -dependent activation of the autophagy initiation complex VPS34 (602609)-beclin-1. Autophagy is completely suppressed in growth plates from Fgf18 -/- embryos, while Fgf18 +/- heterozygous and Fgfr4 -/- mice fail to induce autophagy during postnatal development and show decreased Col2 levels in the growth plate. Strikingly, the Fgf18 +/- and Fgfr4 -/- phenotypes could be rescued in vivo by pharmacologic activation of autophagy, pointing to autophagy as a novel effector of FGF signaling in bone. The data of Cinque et al. (2015) demonstrated that autophagy is a developmentally regulated process necessary for bone growth, and identified FGF signaling as a crucial regulator of autophagy in chondrocytes.
Poillet-Perez et al. (2018) demonstrated that host-specific deletion of Atg7 impairs the growth of multiple allografted tumors, although not all tumor lines were sensitive to host autophagy status. Loss of autophagy in the host was associated with a reduction in circulating arginine, and the sensitive tumor cell lines were arginine auxotrophs owing to the lack of expression of the enzyme argininosuccinate synthase 1. Serum proteomic analysis identified the arginine-degrading enzyme arginase I (ARG1; 608313) in the circulation of Atg7-deficient hosts, and in vivo arginine metabolic tracing demonstrated that serum arginine was degraded to ornithine. ARG1 is predominantly expressed in the liver and can be released from hepatocytes into the circulation. Liver-specific deletion of Atg7 produced circulating Arg1, and reduced both serum arginine and tumor growth. Deletion of Atg5 (604261) in the host similarly regulated circulating arginine and suppressed tumorigenesis, which demonstrated that this phenotype is specific to autophagy function rather than to deletion of Atg7. Dietary supplementation of Atg7-deficient hosts with arginine partially restored levels of circulating arginine and tumor growth. Poillet-Perez et al. (2018) concluded that defective autophagy in the host leads to the release of ARG1 from the liver and the degradation of circulating arginine, which is essential for tumor growth, identifying a metabolic vulnerability of cancer.
In 11 patients from 5 unrelated families with autosomal recessive spinocerebellar ataxia-31 (SCAR31; 619422), Collier et al. (2021) identified homozygous or compound heterozygous mutations in the ATG7 gene (see, e.g., 608760.0001-608760.0007). The mutations were found by exome sequencing, and the patients were ascertained internationally through the GeneMatcher Program. There were 1 nonsense, 2 splice site, and 6 missense mutations. Only 1 family had biallelic complete loss-of-function mutations, although there was not a clear genotype-phenotype correlation. Patient cells showed decreased levels of ATG7 protein associated with defective protein folding and dimerization, and accumulation of p62 (SQSTM1; 601530) in puncta. Functional studies of patient cells demonstrated impaired autophagic flux and decreased LC3 (MAP1LC3A; 601242) processing compared to controls. Expression of wildtype ATG7 rescued the defects in cells from 1 patient. The mutations were unable to fully rescue the LC3 lipidation and autophagic defects in Atg7-knockout mouse cells, consistent with a functional deficiency. Similar studies in yeast showed that the ATG7 mutations were associated with attenuated autophagy. Collier et al. (2021) concluded that impaired intracellular autophagy resulting from ATG7 mutations underlies the complex neurodevelopmental disorder and other organ system involvement observed in these patients.
Komatsu et al. (2006) reported that loss of ATG7, a gene essential for autophagy, leads to neurodegeneration. They found that mice lacking Atg7 specifically in the central nervous system showed behavioral defects, including abnormal limb clasping reflexes and a reduction in coordinated movement, and died with 28 weeks of birth. Atg7 deficiency caused massive neuronal loss in the cerebral and cerebellar cortices. Notably, polyubiquitinated proteins accumulated in autophagy-deficient neurons as inclusion bodies, which increased in size and number with aging. Komatsu et al. (2006) commented that there was no obvious alteration in proteasome function. The authors concluded that autophagy is essential for the survival of neural cells, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies.
Komatsu et al. (2007) found that conditional knockout mice with Purkinje cell-specific deletion of Atg7 developed abnormal axonal swellings and dystrophy of Purkinje cell axon terminals in the deep cerebellar nuclei. The distal axons of Purkinje cells in the knockout mice accumulated aberrant membranous structures that were different from double-membrane vacuole-like structures found in the distal axons of Purkinje cells from wildtype animals. The findings indicated impaired autophagic activity in the axons of mutant cells, which resulted in cell-autonomous axonopathy and Purkinje cell death. Dendritic spines were comparatively much less affected. Mutant mice subsequently developed deficits in locomotion and motor coordination. Komatsu et al. (2007) concluded that autophagy is required for normal axon terminal membrane trafficking and turnover and plays an essential role in the maintenance of axonal homeostasis and prevention of axonal degeneration.
Cadwell et al. (2009) generated mice with a conditional deletion of Atg7 in the intestinal epithelium and observed that the ileal pathology was indistinguishable from that of mice with disruption of Atg16l1 (610767) or Atg5: the Paneth cells displayed a reduced number of granules, dramatically increased cytoplasmic vesicles, abnormal mitochondria, and lysozyme (153450) with striking defects in distribution including diffuse cytoplasmic expression. Cadwell et al. (2009) concluded that a defect in the autophagy pathway in the intestinal epithelium is responsible for the observed Paneth cell pathology.
In 2 sisters, born of unrelated parents (family 1), with autosomal recessive spinocerebellar ataxia-31 (SCAR31; 619422), Collier et al. (2021) identified compound heterozygous loss-of-function mutations in the ATG7 gene: a c.1975C-T transition (c.1975C-T, NM_006395.2), resulting in an arg659-to-ter (R659X) substitution at the extreme C-terminal domain, and an A-to-G transition in intron 18 (c.2080-2A-G; 608760.0002), resulting in a splicing defect and premature termination. The mutations, which were found by exome sequencing, were filtered against public databases. ATG7 protein was undetectable in patient skeletal muscle tissue and fibroblasts. Detailed studies of patient-derived fibroblasts and cell and yeast models in which the mutations were expressed demonstrated a functional ATG7 deficiency and impaired autophagic flux.
For discussion of the A-to-G transition in intron 18 of the ATG7 gene (c.2080-2A-G, NM_006395.2), resulting in a splicing defect and premature termination, that was found in compound heterozygous state in 2 sisters with autosomal recessive spinocerebellar ataxia-31 (SCAR31; 619422) by Collier et al. (2021), see 608760.0001.
In 2 sisters, born of unrelated parents (family 2), with autosomal recessive spinocerebellar ataxia-31 (SCAR31; 619422), Collier et al. (2021) identified compound heterozygous missense mutations in the ATG7 gene: a c.1727G-A transition (c.1727G-A, NM_006395.2), resulting in an arg576-to-his (R576H) substitution, and a c.1870C-T transition, resulting in a his624-to-tyr (H624Y; 608760.0004) substitution. The mutations, which were found by exome sequencing, affected highly conserved residues in the adenylation domain. Detailed studies of patient-derived fibroblasts and cell and yeast models in which the mutations were expressed demonstrated a functional ATG7 deficiency and impaired autophagic flux. The patients had a severe phenotype with global developmental delay, inability to walk or speak, ataxia, spastic paraplegia, and retinopathy.
For discussion of the c.1870C-T transition (c.1870C-T, NM_006395.2) in the ATG7 gene, resulting in a his624-to-tyr (H624Y) substitution, that was found in compound heterozygous state in 2 sisters with autosomal recessive spinocerebellar ataxia-31 (SCAR31; 619422) by Collier et al. (2021), see 608760.0003.
In 2 German adult sibs, born of unrelated parents (family 4), with autosomal recessive spinocerebellar ataxia-31 (SCAR31; 619422), Collier et al. (2021) identified compound heterozygous mutations in the ATG7 gene. One allele carried a c.782A-G transition (c.782A-G, NM_006395.2), predicted to result in a gln261-to-arg (Q261R) substitution, but also disrupting exonic splicing enhancer sites that lead to skipping of exon 8; this splicing defect was confirmed by RT-PCR and Sanger sequencing. The other allele carried a c.1532G-A transition, resulting in a gly511-to-asp (G511D; 608760.0006) substitution at a conserved residue in the adenylation domain. The mutations were found by exome sequencing. Detailed studies of patient-derived fibroblasts and cell and yeast models in which the mutations were expressed demonstrated a functional ATG7 deficiency and impaired autophagic flux.
For discussion of the c.1532G-A transition (c.1532G-A, NM_006395.2) in the ATG7 gene, resulting in a gly511-to-asp (G511D) substitution, that was found in compound heterozygous state in 2 sibs with autosomal recessive spinocerebellar ataxia-31 (SCAR31; 619422) by Collier et al. (2021), see 608760.0005.
In 4 sibs, born of consanguineous Saudi parents (family 5), with autosomal recessive spinocerebellar ataxia-31 (SCAR31; 619422), Collier et al. (2021) identified a homozygous c.1535T-C transition (c.1535T-C, NM_006395.2) in the ATG7 gene, resulting in a leu512-to-pro (L512P) substitution at a highly conserved residue. The mutation, which was found by exome sequencing, occurred in the adenylation domain. Detailed studies of patient-derived fibroblasts and cell and yeast models in which the mutations were expressed demonstrated a functional ATG7 deficiency and impaired autophagic flux.
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Cinque, L., Forrester, A., Bartolomeo, R., Svelto, M., Venditti, R., Montefusco, S., Polishchuk, E., Nusco, E., Rossi, A., Medina, D. L., Polishchuk, R., De Matteis, M. A., Settembre, C. FGF signalling regulates bone growth through autophagy. Nature 528: 272-275, 2015. [PubMed: 26595272] [Full Text: https://doi.org/10.1038/nature16063]
Collier, J. J., Guissart, C., Olahova, M., Sasorith, S., Piron-Prunier, F., Suomi, F., Zhang, D., Martinez-Lopez, N., Leboucq, N., Bahr, A., Azzarello-Burri, S., Reich, S., and 21 others. Developmental consequences of defective ATG7-mediated autophagy in humans. New Eng. J. Med. 384: 2406-2417, 2021. [PubMed: 34161705] [Full Text: https://doi.org/10.1056/NEJMoa1915722]
Gross, M. B. Personal Communication. Baltimore, Md. 5/9/2012.
Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., Tanaka, K. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441: 880-884, 2006. [PubMed: 16625205] [Full Text: https://doi.org/10.1038/nature04723]
Komatsu, M., Wang, Q. J., Holstein, G. R., Friedrich, V. L., Jr., Iwata, J., Kominami, E., Chait, B. T., Tanaka, K., Yue, Z. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc. Nat. Acad. Sci. 104: 14489-14494, 2007. [PubMed: 17726112] [Full Text: https://doi.org/10.1073/pnas.0701311104]
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Yu, L., Alva, A., Su, H., Dutt, P., Freundt, E., Welsh, S., Baehrecke, E. H., Lenardo, M. J. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304: 1500-1502, 2004. [PubMed: 15131264] [Full Text: https://doi.org/10.1126/science.1096645]
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