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
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Molecular and Human Genetics, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
Am J Hum Genet. 2016 Oct 6;99(4):831-845. doi: 10.1016/j.ajhg.2016.08.007. Epub 2016 Sep 15.
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, 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 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.
含ATP酶家族AAA结构域蛋白3A（ATAD3A）是一种核编码的线粒体膜蛋白，与线粒体动力学、类核组织、蛋白质翻译、细胞生长和胆固醇代谢有关。我们通过全外显子组测序（WES）在五名无亲缘关系的个体中鉴定出一种反复出现的新生ATAD3A c.1582C>T（p.Arg528Trp）变异，这些个体具有全球发育迟缓、肌张力减退、视神经萎缩、轴索性神经病和肥厚型心肌病的核心表型。我们还描述了两个携带ATAD3A双等位基因变异的家系，包括两名兄弟姐妹中的纯合变异，以及由ATAD3A与基因家族成员ATAD3B和ATAD3C之间的非等位基因同源重组（NAHR）介导的双等位基因ATAD3A缺失。果蝇中与人类c.1582C>T（p.Arg528Trp）变异同源的bor基因在组织特异性过表达后，导致线粒体含量显著减少、线粒体形态异常和自噬增加。纯合缺失bor的幼虫线粒体显著减少，而bor过表达则导致线粒体更大、更长。最后，一名受影响个体的成纤维细胞表现出线粒体自噬增加。我们得出结论，p.Arg528Trp变异通过显性负性机制发挥作用，导致线粒体变小并触发线粒体自噬，从而导致线粒体含量减少。ATAD3A变异代表了线粒体动力学与可识别的神经综合征之间的另一个联系纽带，就像MFN2、OPA1、DNM1L和STAT2突变的情况一样。
