VRK 1基因c.1124G>A纯合突变导致远端型遗传性运动神经病一家系遗传学分析

Genetic analysis of a pedigree with VRK 1 gene c.1124G>A homozygous mutation induced distal hereditary motor neuropathy

目的分析一家系2例远端型遗传性运动神经病(distal hereditary motor neuropathy,dHMN)患者临床特征,探讨牛痘相关激酶1(vaccinia-related kinase 1,VRK1)基因突变情况。方法收集一家系2例dHMN患者临床资料。采集先证者及其父母、女儿外周血,提取基因组DNA,进行全外显子组测序及生物信息学分析,采用Sanger测序进行验证。结果先证者双下肢肌萎缩并逐渐加重,感觉无异常。先证者弟弟有类似症状及体征,父母及女儿无相关症状及体征。先证者存在VRK1基因c.1124G>A位点纯合突变;先证者父母及其女儿均存在VRK1基因c.1124G>A位点杂合突变;先证者弟弟未行全外显子组测序及Sanger测序。该突变为已报道致病性突变;该突变使VRK1蛋白C端第375位色氨酸变为终止密码子(p.W375X),导致VRK1蛋白部分功能缺失,为无义突变。结论VRK1基因c.1124G>A(p.W375X)位点纯合突变可能是该家系2例dHMN患者的致病原因;VRK1基因突变导致dHMN患者的临床表型存在异质性。

Objective To analyze the clinical features of two patients with distal hereditary motor neuropathy(dHMN)in a family,and to investigate the mutation of vaccinia-related kinase 1(VRK1)gene.Methods The clinical data of two dHMN patients in a family were collected.Genomic DNA was extracted from peripheral blood of the proband,his parents and daughter.Whole exome sequencing and bioinformatics analysis were performed,and Sanger sequencing was used for verification.Results The proband's muscles in both lower limbs atrophied and gradually worsened with no abnormal feeling.His young brother had similar symptoms and signs,and his parents and daughter had no similar symptoms and signs.The proband had a homozygous mutation at c.1124G>A locus of VRK1 gene,his parents and daughter had a heterozygous mutation of VRK1 gene c.1124G>A,and his young brother received no whole exome sequencing or Sanger sequencing.The mutation was a nonsense mutation,which was the reported pathogenic mutation.This mutation changed the 375th tryptophan at the C-terminal of VRK1protein into a stop codon(p.W375X),resulting in partial loss of function of VRK1protein.Conclusion The homozygous mutation of VRK1 gene c.1124G>A(p.W375X)may be the cause of two dHMN patients in this family,and VRK1 gene mutation leads to heterogeneity in the clinical phenotype of dHMN patients.