人类NARS2的突变,编码线粒体asparaginyl-tRNA合成酶,导致nonsyndromic耳聋和利综合症。
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理查德·西蒙•M EM,王X,沙赫扎德,黄VH,凯伊斯助教,Potluri P, Mahl SE,戴维拉,萨年代,汉考克年代,余米,Gargus J, Chang R, Al-Sheqaih N,纽曼工作组,Abdenur J,斯塔尔,对冲基金R,多恩T,布施,公园E,吴J, Schwenzer H, Flierl, Florentz C, Sissler M,汗SN,李R,关MX,弗里德曼结核病,吴DK, Procaccio V, Riazuddin年代,华莱士,艾哈迈德ZM评选,黄T, Riazuddin年代
人类NARS2的突变,编码线粒体asparaginyl-tRNA合成酶,导致nonsyndromic耳聋和利综合症。
公共科学图书馆麝猫。2015年3月25日,11 (3):e1005097。doi: 10.1371 / journal.pgen.1005097。eCollection 2015年3月。
- PubMed ID
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25807530 (在PubMed]
- 文摘
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这里我们展示协会的变异线粒体asparaginyl-tRNA合成酶NARS2与人类的听力损失和利综合症。一个纯合子的错义突变([c.637G > T;p.Val213Phe])是nonsyndromic听力损失的根本原因(DFNB94)和复合的杂合突变([c.969T >;p。Tyr323 *] + [c.1142A > G;p.Asn381Ser])导致线粒体呼吸链缺陷和利综合征,这是一种神经退行性疾病的特点是对称的,双方在基底神经节病变,丘脑和脑干。遗传病变的严重程度及其影响NARS2蛋白质结构cosegregate表型。一个假想的截断NARS2蛋白质,次要的利综合征突变p。Tyr323 *不是可检测和p。Asn381Ser进一步减少NARS2患者成纤维细胞中蛋白质含量。p。Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNAAsn in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome.