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
Volume99
Issue4
Pagination831-845
Date Published2016 Oct 06
ISSN1537-6605
Abstract

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(R534W), 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(WT) 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.

DOI10.1016/j.ajhg.2016.08.007
Alternate JournalAm. J. Hum. Genet.
PubMed ID27640307
PubMed Central IDPMC5065660
Grant ListU54 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
UM1 HG006542 / HG / NHGRI 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