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

Am J Hum Genet
Authors
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
Journal
Am J Hum Genet
Volume
99
Issue
4
Pages
831-845
Date Published
2016 Oct 06
ISSN
1537-6605
DOI
10.1016/j.ajhg.2016.08.007
PubMed ID
27640307
PubMed Central ID
PMC5065660
Links
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