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Harel, Tamar; Yoon, Wan Hee; Garone, Caterina; Gu, Shen; Coban-Akdemir, Zeynep; Eldomery, Mohammad K.; Posey, Jennifer E.; Jhangiani, Shalini N.; Rosenfeld, Jill A.; Cho, Megan T.; Fox, Stephanie; Withers, Marjorie; Brooks, Stephanie M.; Chiang, Theodore; Duraine, Lita; Erdin, Serkan; Yuan, Bo; Shao, Yunru; Moussallem, Elie; Lamperti, Costanza; Donati, Maria A.; Smith, Joshua D.; McLaughlin, Heather M.; Eng, Christine M.; Walkiewicz, Magdalena; Xia, Fan; Pippucci, Tommaso; Magini, Pamela; Seri, Marco; Zeviani, Massimo; Hirano, Michio; Hunter, Jill V.; Srour, Myriam; Zanigni, Stefano; Lewis, Richard Alan; Muzny, Donna M.; Lotze, Timothy E.; Boerwinkle, Eric; Gibbs, Richard A.; Hickey, Scott E.; Graham, Brett H.; Yang, Yaping; Buhas, Daniela; Martin, Donna M.; Potocki, Lorraine; Graziano, Claudio; Bellen, Hugo J.; Lupski, James R.
American journal of human genetics, 10/2016, Letnik: 99, Številka: 4Journal Article
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 borR534W, 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 borWT 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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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