Bi-allelic loss of function variants in COX20 gene cause autosomal recessive sensory neuronopathy
Bi-allelic loss of function variants in COX20 gene cause autosomal recessive sensory neuronopathy
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DOI：
10.1093/brain/awab135
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发表时间：
2021-03-22
期刊：
影响因子：
14.5
通讯作者：
Wu, Zhi-Ying
中科院分区：
文献类型：
--
作者：
Dong, Hai-Lin;Ma, Yin;Wu, Zhi-Ying
感觉神经元病是一种罕见的和独特的亚组周围神经病，其特征是背根神经节神经元的变性。大约50%的感觉神经元病是特发性的，遗传原因仍有待澄清。通过纯合性作图和全外显子组测序的结合，我们将一种常染色体隐性遗传的感觉神经元病与COX20基因的致病性变异联系起来，我们从中国东部人群中鉴定出8个携带创始者变异c.41A> G的不相关家族（p.Lys14Arg）在纯合或复合杂合状态的COX20内。所有患者均表现为感觉性共济失调，非长度依赖性感觉电位降低。COX20编码一个关键的跨膜蛋白，参与线粒体复合物IV的组装。我们发现，COX20变体导致患者成纤维细胞和转染细胞系中COX20蛋白的减少，这与功能丧失机制一致。ND7/23感觉神经元细胞中COX20表达的敲低导致复合物IV缺陷和复合物IV的扰乱组装，其随后损害细胞备用呼吸能力并降低代谢应激下的细胞增殖。与敲低细胞中的线粒体功能障碍一致，在患者的成纤维细胞中也发现了复合物IV组装、酶活性和耗氧速率的降低。推测COX20的作用机制与其他致病基因相似（例如SURF 1、COX6A1、COA 3和SCO2），所有这些在复合物IV的结构和组装中具有重要的功能。我们的研究鉴定了常染色体隐性感觉神经元病的新致病基因，其在复合体IV中的重要功能和在本体感觉神经元中的高表达进一步强调了作为外周感觉神经元中的机制的导致线粒体生物能量功能障碍的COX20的损失疾病
Sensory neuronopathies are a rare and distinct subgroup of peripheral neuropathies, characterized by degeneration of the dorsal root ganglia neurons. About 50% of sensory neuronopathies are idiopathic and genetic causes remain to be clarified.Through a combination of homozygosity mapping and whole exome sequencing, we linked an autosomal recessive sensory neuronopathy to pathogenic variants in the COX20 gene.We identified eight unrelated families from the eastern Chinese population carrying a founder variant c.41A > G (p.Lys14Arg) within COX20 in either a homozygous or compound heterozygous state. All patients displayed sensory ataxia with a decrease in non-length-dependent sensory potentials. COX20 encodes a key transmembrane protein implicated in the assembly of mitochondrial complex IV. We showed that COX20 variants lead to reduction of COX20 protein in patient's fibroblasts and transfected cell lines, consistent with a loss-of-function mechanism. Knockdown of COX20 expression in ND7/23 sensory neuron cells resulted in complex IV deficiency and perturbed assembly of complex IV, which subsequently compromised cell spare respiratory capacity and reduced cell proliferation under metabolic stress. Consistent with mitochondrial dysfunction in knockdown cells, reduced complex IV assembly, enzyme activity and oxygen consumption rate were also found in patients' fibroblasts. We speculated that the mechanism of COX20 was similar to other causative genes (e.g. SURF1, COX6A1, COA3 and SCO2) for peripheral neuropathies, all of which are functionally important in the structure and assembly of complex IV.Our study identifies a novel causative gene for the autosomal recessive sensory neuronopathy, whose vital function in complex IV and high expression in the proprioceptive sensory neuron further underlines loss of COX20 contributing to mitochondrial bioenergetic dysfunction as a mechanism in peripheral sensory neuron disease.