Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder.
Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder.
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DOI：
10.1038/ng.3354
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发表时间：
2015-08
期刊：
影响因子：
30.8
通讯作者：
Dallman JE
中科院分区：
文献类型：
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作者：
Abrams AJ;Hufnagel RB;Rebelo A;Zanna C;Patel N;Gonzalez MA;Campeanu IJ;Griffin LB;Groenewald S;Strickland AV;Tao F;Speziani F;Abreu L;Schüle R;Caporali L;La Morgia C;Maresca A;Liguori R;Lodi R;Ahmed ZM;Sund KL;Wang X;Krueger LA;Peng Y;Prada CE;Prows CA;Schorry EK;Antonellis A;Zimmerman HH;Abdul-Rahman OA;Yang Y;Downes SM;Prince J;Fontanesi F;Barrientos A;Németh AH;Carelli V;Huang T;Zuchner S;Dallman JE
显性视神经萎缩（DOA）和轴突周围神经病变（Charcot-Marie-Tooth 2型或CMT 2）是遗传性神经退行性疾病，最常见的是分别由经典线粒体融合基因OPA 1和MFN 2突变引起的。在酵母中，OPA 1（Mgm 1）和MFN 2（Fzo 1）的同源物与Ugo 1协同工作，而Ugo 1迄今为止还没有人类等效物。通过全外显子组测序，我们发现了4个具有SLC 25 A46隐性突变的视神经萎缩和CMT 2患者家系。我们证明，SLC 25 A46，像Ugo 1，是一种修饰的载体蛋白，已被招募到外线粒体膜和内膜重塑蛋白，丝裂素（Fcj 1）相互作用。培养细胞和斑马鱼的功能丧失意外地导致线粒体连接增加，同时严重影响鱼类神经元的发育和维持。SLC 25 A46的发现加强了视神经萎缩和CMT 2之间的遗传重叠，同时例证了一类与线粒体动力学相关的新型修饰的溶质转运蛋白。
Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth Type 2 or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1(Mgm1) and MFN2(Fzo1) work in concert with Ugo1, which has no human equivalent to date. By whole exome sequencing patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein, mitofilin(Fcj1). Loss-of-function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2, while exemplifying a novel class of modified solute transporters linked to mitochondrial dynamics.