Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, 310009, Hangzhou, China.
NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
Brain. 2021 Sep 4;144(8):2457-2470. doi: 10.1093/brain/awab135.
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.
感觉神经元病是一种罕见且独特的周围神经病亚组，其特征是背根神经节神经元变性。大约 50%的感觉神经元病是特发性的，遗传原因仍有待阐明。通过纯合子作图和全外显子组测序的结合，我们将一种常染色体隐性感觉神经元病与 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了 8 个无亲缘关系的家族，这些家族在 COX20 中携带一个奠基者变异 c.41A>G（p.Lys14Arg），无论是纯合子还是复合杂合子状态。所有患者均表现出感觉性共济失调，非长度依赖性感觉电位下降。COX20 编码一种关键的跨膜蛋白，参与线粒体复合物 IV 的组装。我们表明 COX20 变体导致患者成纤维细胞和转染细胞系中的 COX20 蛋白减少，符合功能丧失机制。在 ND7/23 感觉神经元细胞中敲低 COX20 表达导致复合物 IV 缺陷和复合物 IV 组装紊乱，随后损害细胞备用呼吸能力，并在代谢应激下降低细胞增殖。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 组装减少、酶活性和耗氧量降低。我们推测 COX20 的机制与其他导致周围神经病的致病基因（如 SURF1、COX6A1、COA3 和 SCO2）相似，所有这些基因在复合物 IV 的结构和组装中都具有重要功能。我们的研究确定了一种常染色体隐性感觉神经元病的新致病基因，其在复合物 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 COX20 的缺失导致线粒体生物能功能障碍作为周围感觉神经元疾病的一种机制。
