Whole-exome sequencing identifies a heterozygous mutation in SLC12A6 associated with hereditary sensory and motor neuropathy
Whole-exome sequencing identifies a heterozygous mutation in SLC12A6 associated with hereditary sensory and motor neuropathy
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DOI：
10.1016/j.nmd.2020.11.002
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发表时间：
2021-02-06
影响因子：
2.8
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
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作者：
Shi, Jiaying;Zhao, Fei;Zhang, Wei
腓骨肌萎缩症（CMT）是一种表型和遗传异质性周围神经系统疾病。据报道，SLC 12 A6中的双等位基因变体是常染色体隐性（AR）遗传性运动和感觉神经病伴胼胝体发育不全（HMSN/ACC）的原因。我们在一例中度CMT中国患者中发现了SLC 12 A6的常染色体显性（AD）杂合突变。患者出现缓慢进行性远端肌无力和萎缩。电生理检查显示混合轴突/脱髓鞘神经病变。认知和脑部MRI正常。SLC 12 A6外显子5中的一个单一杂合错义突变c.620G > A（p.R207H）通过全外显子组测序被鉴定为可能的致病突变，与先前发表的两个病例一致。它影响进化上高度保守的氨基酸残基，并且通过使用计算机工具预测是有害的。突变KCC 3协同转运蛋白的建模显示，改变了氢键的形成，并削弱了突变位点与其周围氨基酸残基之间的相互作用力。我们的研究结果扩展了与SLC 12 A6突变相关的基因型和表型谱，从AR-HMSN/ACC到AD-CMT。遗传模式的差异可能与显性-阴性病理机制有关。(c)2020爱思唯尔B. V.保留所有权利。
Charcot-Marie-Tooth disease (CMT) represents a phenotypically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been reported as the cause of autosomal-recessive (AR) hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). Here we identified an autosomal-dominant (AD) heterozygous mutation in SLC12A6 in a Chinese patient with intermediate CMT. The patient presented with slowly progressive distal muscle weakness and atrophy. Electrophysiological examination showed a mixed axonal/demyelinating neuropathy. Cognition and brain MRI were normal. A single heterozygous missense mutation c.620G > A (p.R207H) in exon 5 of SLC12A6 was identified as the likely pathogenic mutation by whole-exome sequencing consistent with two previously published cases. It affects evolutionarily highly conserved amino acid residue and is predicted to be deleterious by using in silico tools. Modelling of the mutant KCC3 cotransporter showed altered formation of hydrogen bonds and weakened interaction force between the mutated site and its surrounding amino acid residues. Our findings expand the genotypic and phenotypic spectrum associated with SLC12A6 mutations from AR-HMSN/ACC to AD-CMT. The differences in the inheritance pattern might be associated with a dominant-negative pathomechanism. (c) 2020 Elsevier B.V. All rights reserved.