Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.
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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. |
Year of Publication | 2016
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Journal | Am J Hum Genet
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Volume | 99
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Issue | 4
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Pages | 831-845
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Date Published | 2016 Oct 06
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ISSN | 1537-6605
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DOI | 10.1016/j.ajhg.2016.08.007
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PubMed ID | 27640307
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PubMed Central ID | PMC5065660
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Grant list | 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
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
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