Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy.
Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy.
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DOI：
10.1093/hmg/ddx377
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发表时间：
2017-12-15
影响因子：
3.5
通讯作者：
Huang T
中科院分区：
文献类型：
--
作者：
Peng Y;Shinde DN;Valencia CA;Mo JS;Rosenfeld J;Truitt Cho M;Chamberlin A;Li Z;Liu J;Gui B;Brockhage R;Basinger A;Alvarez-Leon B;Heydemann P;Magoulas PL;Lewis AM;Scaglia F;Gril S;Chong SC;Bower M;Monaghan KG;Willaert R;Plona MR;Dineen R;Milan F;Hoganson G;Powis Z;Helbig KL;Keller-Ramey J;Harris B;Anderson LC;Green T;Sukoff Rizzo SJ;Kaylor J;Chen J;Guan MX;Sellars E;Sparagana SP;Gibson JB;Reinholdt LG;Tang S;Huang T
铁硫簇（Fe-S）是各种细胞过程中必不可少的普遍存在的辅因子，包括线粒体呼吸，DNA修复和铁稳态。一个稳步增加的疾病数量正在与破坏Fe-S集群的生物成因。在这里，我们进行了全外显子组测序的患者与视神经萎缩和其他神经系统症状的视网膜病变，并确定了17个人从13个不相关的家庭隐性突变FDXR，编码线粒体膜相关的黄素蛋白铁氧还蛋白还原酶所需的电子转运从NADPH到细胞色素P450。患者成纤维细胞中的体外酶促测定显示铁氧还蛋白NADP还原酶活性不足和线粒体功能障碍，表现为低耗氧率（OCR）、复合物活性、ATP产生和活性氧（ROS）增加。这种缺陷通过野生型FDXR的过表达而得到挽救。此外，我们发现，携带与患者中发现的最常见突变等位的自发突变的小鼠显示进行性步态异常和视力丧失，此外还有与该疾病的主要临床特征一致的生化缺陷。总而言之，这些数据首次证明FDXR中的种系亚型突变会导致人类新型线粒体病和视神经萎缩。
Iron–sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe–S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans.
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影响因子：
4.8
作者：
Griffin A;Parajes S;Weger M;Zaucker A;Taylor AE;O'Neil DM;Müller F;Krone N
通讯作者：
Krone N
人线粒体铁蛋白1（FDX1）和铁氧还蛋白2（FDX2）都结合半胱氨酸脱硫酶，并捐赠电子以用于铁硫簇生物合成。
影响因子：
2.9
作者：
Cai K;Tonelli M;Frederick RO;Markley JL
通讯作者：
Markley JL
IBS：用于生物序列呈现和可视化的插画家
DOI：
10.1093/bioinformatics/btv362
发表时间：
2015-10-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Liu W;Xie Y;Ma J;Luo X;Nie P;Zuo Z;Lahrmann U;Zhao Q;Zheng Y;Zhao Y;Xue Y;Ren J
通讯作者：
Ren J
影响因子：
16
作者：
Land, T;Rouault, TA
通讯作者：
Rouault, TA
DOI：
10.1042/bj20100122
发表时间：
2010-04-28
期刊：
The Biochemical journal
影响因子：
--
作者：
Lu J;Bitoun JP;Tan G;Wang W;Min W;Ding H
通讯作者：
Ding H