Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.

TitleRecurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.
Publication TypeJournal Article
Year of Publication2016
AuthorsHarel, T, Yoon, WHee, Garone, C, Gu, S, Coban-Akdemir, Z, Eldomery, MK, Posey, JE, Jhangiani, SN, Rosenfeld, JA, Cho, MT, Fox, S, Withers, M, Brooks, SM, Chiang, T, Duraine, L, Erdin, S, Yuan, B, Shao, Y, Moussallem, E, Lamperti, C, Donati, MA, Smith, JD, McLaughlin, HM, Eng, CM, Walkiewicz, M, Xia, F, Pippucci, T, Magini, P, Seri, M, Zeviani, M, Hirano, M, Hunter, JV, Srour, M, Zanigni, S, Lewis, RAlan, Muzny, DM, Lotze, TE, Boerwinkle, E, Gibbs, RA, Hickey, SE, Graham, BH, Yang, Y, Buhas, D, Martin, DM, Potocki, L, Graziano, C, Bellen, HJ, Lupski, JR
Corporate AuthorsBaylor-Hopkins Center for Mendelian Genomics, University of Washington Center for Mendelian Genomics
JournalAm J Hum Genet
Date Published2016 Oct 06
KeywordsAdenosine Triphosphatases, Adult, Alleles, Animals, ATPases Associated with Diverse Cellular Activities, Axons, Cardiomyopathies, Child, Child, Preschool, Developmental Disabilities, DNA Copy Number Variations, Drosophila melanogaster, Female, Fibroblasts, Homozygote, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Muscle Hypotonia, Muscles, Mutation, Nervous System Diseases, Neurons, Optic Atrophy, Phenotype, Polymorphism, Single Nucleotide, Syndrome, Young Adult

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of bor, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of bor resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

Alternate JournalAm J Hum Genet
PubMed ID27640307
PubMed Central IDPMC5065660
Grant ListMC_UP_1002/1 / MRC_ / Medical Research Council / United Kingdom
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
U54 NS093793 / NS / NINDS NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
R01 DC009410 / DC / NIDCD NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States

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