A novel DNAJB6 mutation causes dominantly inherited distal‐onset myopathy and compromises DNAJB6 function

• Published in: Clinical genetics Vol. 92; no. 2; pp. 150 - 157
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2017
• Subjects: Adult; Age of Onset; Amino acids; Distal Myopathies - diagnostic imaging; Distal Myopathies - genetics; Distal Myopathies - physiopathology; distal‐onset myopathy; DNAJB6; exome sequencing; Female; Genetic Predisposition to Disease; Glycine; HSP40 Heat-Shock Proteins - genetics; Humans; Immunofluorescence; LGMD; limb‐girdle muscular dystrophy; Magnetic Resonance Imaging; Male; Molecular Chaperones - genetics; Muscle, Skeletal - diagnostic imaging; Muscle, Skeletal - physiopathology; Muscular dystrophy; Mutation; Mutation, Missense - genetics; Myopathy; Nerve Tissue Proteins - genetics; Phenylalanine; Studies; Whole Exome Sequencing; LGMD; exome sequencing; DNAJB6; myopathy; distal-onset myopathy; limb-girdle muscular dystrophy
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.13001

Background Mutations in the DNAJB6 gene have been identified as a rare cause of dominantly inherited limb‐girdle muscular dystrophy or distal‐onset myopathy. Materials and Methods 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. Results 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. Conclusion This study expands the molecular spectrum of DNAJB6 mutations and also emphasizes the pathogenic role of DNAJB6 dysfunction in distal‐onset myopathy.