Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related (ATG) genes in mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range of complex human diseases, yet congenital autophagy disorders are rare.
Scientists performed a genetic, clinical, and neuroimaging analysis involving five families. Mechanistic investigations were conducted with the use of patient-derived fibroblasts, skeletal muscle–biopsy specimens, mouse embryonic fibroblasts, and yeast.
They found deleterious, recessive variants in human ATG7, a core autophagy-related gene encoding a protein that is indispensable to classical degradative autophagy. Twelve patients from five families with distinct ATG7 variants had complex neurodevelopmental disorders with brain, muscle, and endocrine involvement. Patients had abnormalities of the cerebellum and corpus callosum and various degrees of facial dysmorphism. These patients have survived with impaired autophagic flux arising from a diminishment or absence of ATG7 protein. Although autophagic sequestration was markedly reduced, evidence of basal autophagy was readily identified in fibroblasts and skeletal muscle with loss of ATG7. Complementation of different model systems by deleterious ATG7 variants resulted in poor or absent autophagic function as compared with the reintroduction of wild-type ATG7.
They identified several patients with a neurodevelopmental disorder who have survived with a severe loss or complete absence of ATG7, an essential effector enzyme for autophagy without a known functional paralogue. (Funded by the Wellcome Centre for Mitochondrial Research and others.)
Acroautophagy (hereafter “autophagy”) serves to protect the cell from cytotoxicity through degradation of toxic protein aggregates, pathogens, and damaged organelles. It also sustains homeostasis by recycling essential metabolites. Autophagy involves the formation of a transient double membrane–bound autophagosome that encapsulates and delivers cytoplasmic cargo to acidic subcompartments of the endolysosomal system for degradation by hydrolysis. A core set of autophagy-related (ATG) genes orchestrates the fundamental stages of canonical autophagy.
Approximately 20 core ATG genes are conserved across eukaryotes and are critical to the process of canonical autophagy, yet only 4 of these genes (ATG5, WDR45, WDR45B, and WIPI2) are implicated in mendelian disease. The identification of cohorts of patients with autophagy deficiencies provides an opportunity to investigate the systemic role of core autophagy-related proteins. An understanding of the clinical and functional profiles in such patients could provide further insights into the etiologic links between aberrant autophagy and the many complex disease states it is predicted to underpin, from neurodegeneration to cancer. Indeed, access to biologic specimens from patients with autophagy deficiencies might also accelerate the development of autophagy-augmenting therapeutics.
The Unc-51–like kinase 1 (ULK1) complex integrates multiple upstream signals and transmits them to initiate canonical autophagy, which depends on ubiquitin-like conjugation systems to drive autophagosome biogenesis. ATG7 encodes an E1-like enzyme that activates ATG12 before its conjugation to ATG5, promoting expansion of the preautophagosomal phagophore. ATG7 also facilitates lipidation of the protein LC3-I with phosphatidylethanolamine to generate LC3-II, which is found on the inner and outer autophagosomal membranes and recruits cytoplasmic cargo to the autophagosome either directly or through selective adaptor proteins. Studies in mice have shown the physiological significance of endogenous ATG7; Atg7-null mice die within 24 hours after birth. Thus, autophagy is regarded as an essential process in mammals. The subsequent characterization of mouse models has revealed the profound importance of Atg7 in nerve and muscle, wherein tissue-specific Atg7 ablation leads to ataxia and myopathy, respectively. Classically, the loss of mammalian ATG7 is regarded as rendering cells and tissues “autophagy-deficient.”
They report the discovery of five unrelated families with recessive ATG7 variants that were both deleterious (i.e., predicted to reduce fitness, as determined by cross-species comparison of protein sequences) and damaging (i.e., shown through biochemical assays to interfere with the function of the protein). Affected family members had a neurodevelopmental syndrome that was distinguished by cerebellar hypoplasia, a thin posterior corpus callosum, ataxia, developmental delay, musculoskeletal abnormalities, and facial dysmorphism. Their study has been published in The NEW ENGLAND JOURNAL of MEDICINE.
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