Tsai P-C, Tsai Y-S, Soong B-W, Huang Y-H, Wu H-T, Chen Y-H, Lin K-P, Liao Y-C, Lee Y-C
Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan.
Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
Clin Genet. 2017 Aug;92(2):150-157. doi: 10.1111/cge.13001. Epub 2017 Apr 12.
Mutations in the DNAJB6 gene have been identified as a rare cause of dominantly inherited limb-girdle muscular dystrophy or distal-onset myopathy.
Exome sequencing was performed to investigate a Taiwanese family with a dominantly inherited distal-onset myopathy. Functional effects of the causal mutation were investigated in vitro.
Exome sequencing of the two affected individuals in this family identified a heterozygous mutation, c.287C>T (p.Pro96Leu) in the DNAJB6 gene, which co-segregated with the myopathy within all 12 family members. Notably, this mutation is novel and localizes within the glycine and phenylalanine-rich (G/F) domain and alters an amino acid residue previously reported with a different mutation. Furthermore, immunofluorescence analyses and filter trap assay demonstrated that the c.287C>T (p.Pro96Leu) mutation possessed a dominant negative effect on the anti-aggregation function of DNAJB6 protein.
This study expands the molecular spectrum of DNAJB6 mutations and also emphasizes the pathogenic role of DNAJB6 dysfunction in distal-onset myopathy.
DNAJB6基因的突变已被确定为显性遗传性肢带型肌营养不良或远端型肌病的罕见病因。
对一个患有显性遗传性远端型肌病的台湾家庭进行外显子组测序。在体外研究了致病突变的功能效应。
对该家庭中两名受影响个体的外显子组测序发现了DNAJB6基因中的一个杂合突变，c.287C>T（p.Pro96Leu），该突变在所有12名家庭成员中与肌病共分离。值得注意的是，这个突变是新发现的，位于富含甘氨酸和苯丙氨酸的（G/F）结构域内，并且改变了一个先前报道有不同突变的氨基酸残基。此外，免疫荧光分析和滤膜截留试验表明，c.287C>T（p.Pro96Leu）突变对DNAJB6蛋白的抗聚集功能具有显性负效应。
本研究扩展了DNAJB6突变的分子谱，同时也强调了DNAJB6功能障碍在远端型肌病中的致病作用。
