Harel, T., Yoon, W.H., Garone, C., Gu, S., Coban-Akdemir, Z., Eldomery, M.K., Posey, J.E., Jhangiani, S.N., Rosenfeld, J.A., Cho, M.T., Fox, S., Withers, M., Brooks, S.M., Chiang, T., Duraine, L., Erdin, S., Yuan, B., Shao, Y., Moussallem, E., Lamperti, C., Donati, M.A., Smith, J.D., McLaughlin, H.M., Eng, C.M., Walkiewicz, M., Xia, F., Pippucci, T., Magini, P., Seri, M., Zeviani, M., Hirano, M., Hunter, J.V., Srour, M., Zanigni, S., Lewis, R.A., Muzny, D.M., Lotze, T.E., Boerwinkle, E., Baylor-Hopkins Center for Mendelian Genomics, , University of Washington Center for Mendelian Genomics, , Gibbs, R.A., Hickey, S.E., Graham, B.H., Yang, Y., Buhas, D., Martin, D.M., Potocki, L., Graziano, C., Bellen, H.J., Lupski, J.R. (2016). Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.  Am. J. Hum. Genet. 99(4): 831--845.

FBrf0233629

Research paper

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.

PMC5065660 (PMC) (EuropePMC)