NDUFA9 point mutations cause a variable mitochondrial complex I assembly defect
NDUFA9 point mutations cause a variable mitochondrial complex I assembly defect
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DOI：
10.1111/cge.13089
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发表时间：
2018-01-01
影响因子：
3.5
通讯作者：
Nijtmans, L. G. J.
中科院分区：
文献类型：
--
作者：
Baertling, F.;Sanchez-Caballero, L.;Nijtmans, L. G. J.
线粒体呼吸链复合物I由44个不同的亚基组成，包含3个功能模块：Q-、N-和P-模块。NDUFA 9是复合物I组装或稳定性所需的Q-模块亚基。然而，其在复合物I生物合成中的作用尚未在患者成纤维细胞中研究。到目前为止，已经报道了一名携带具有严重的脑死亡表型的NDUFA 9变体的患者。通过外显子组测序，我们在另一名轻度表型患者（包括儿童期发作的进行性全身性肌张力障碍和轴突周围神经病变）中鉴定了一种新的纯合NDUFA 9错义变体。我们使用两名患者的原代皮肤成纤维细胞进行复合物I组装分析。两例患者均存在复合物I丰度降低和Q模块子组装积累，但在严重临床表型患者中更为明显。后者显示额外的积累的P-模块，这是不存在于轻度表型患者。两种患者成纤维细胞系与野生型NDUFA 9的慢病毒互补挽救了复合物I缺陷和组装缺陷。我们的报告进一步表征了NDUFA 9缺陷的表型谱，并证明了临床表型的严重程度与不同NDUFA 9变体对复合物I组装的影响的严重程度相关。
Mitochondrial respiratory chain complex I consists of 44 different subunits and contains 3 functional modules: the Q-, the N- and the P-module. NDUFA9 is a Q-module subunit required for complex I assembly or stability. However, its role in complex I biogenesis has not been studied in patient fibroblasts. So far, a single patient carrying an NDUFA9 variant with a severe neonatally fatal phenotype has been reported. Via exome sequencing, we identified a novel homozygous NDUFA9 missense variant in another patient with a milder phenotype including childhood-onset progressive generalized dystonia and axonal peripheral neuropathy. We performed complex I assembly analysis using primary skin fibroblasts of both patients. Reduced complex I abundance and an accumulation of Q-module subassemblies were present in both patients but more pronounced in the severe clinical phenotype patient. The latter displayed additional accumulation of P-module subassemblies, which was not present in the milder-phenotype patient. Lentiviral complementation of both patient fibroblast cell lines with wild-type NDUFA9 rescued complex I deficiency and the assembly defects. Our report further characterizes the phenotypic spectrum of NDUFA9 deficiency and demonstrates that the severity of the clinical phenotype correlates with the severity of the effects of the different NDUFA9 variants on complex I assembly.