Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy

Abstract

IntroductionProtein aggregation is a common cause of neuropathology. The protein aggregation myopathy Limb-Girdle Muscular Dystrophy 1D (LGMD1D) is caused by mutations of amino acids Phe89 or Phe93 of DNAJB6, a co-chaperone of the HSP70 anti-aggregation protein. Another DNAJB6 mutation, Pro96Arg, was found to cause a distal-onset myopathy in one family.ResultsWe detail the mutational, neuropathological, neurophysiological, neurological and radiological features of five new DNAJB6-myopathy families. One has the known Phe93Leu mutation and classic late-onset slowly progressive LGMD1D. Two have different mutations of Phe91 causing a variant childhood-onset severe limb-girdle myopathy. One has a Phe100Val mutation and distal-onset myopathy, unique early bulbar involvement, and a gender-modified wide age-of-onset range. The last has childhood-onset severe distal-onset myopathy and the first non-missense DNAJB6 mutation, c.346 + 5G > A, causing a splicing defect that entirely eliminates DNAJB6’s G/F domain (ΔG/F), the domain that harbours all other mutations. Clinical and imaging examinations reveal that muscles considered uninvolved in DNAJB6-myopathy, e.g. lateral gastrocnemii, are affected in our patients with new mutations. Mutational modelling based on the known structure of the bacterial DNAJ2 protein indicates that all past and present mutated residues cluster within 15 Å in the G/F domain and all disturb the interface of this domain with the protein’s J domain that confers the interaction with HSP70.ConclusionsOur patients expand the phenotypic spectrum of DNAJB6-myopathy and allow tentative genotype-phenotype specifications. Combining with previous studies, the clinical severity spectrum is as follows: ΔG/F and Phe91 mutations, most severe; Phe100, Pro96, Phe89 mutations, intermediate; and Phe93, least severe. As it stands presently, proximal G/F domain mutations (Phe89, Phe91, Phe93) cause proximal limb-girdle myopathy, while distal G/F mutations (Pro96, Phe100) cause distal-onset myopathy. While all mutations affect the G/F–J interaction, each likely does so in different unknown extents or ways. One mutation, ΔG/F, causes its associated severe distal-onset myopathy phenotype in a clear way, through generation of a G/F domain-lacking DNAJB6 protein.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0224-0) contains supplementary material, which is available to authorized users.

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

“…Five other programs: Mutation Taster, PolyPhen‐2, SNPs&GO, SIFT, SNAP2 also predicted the mutation to be disease‐causing. The p.Pro96Leu mutation, as all the previously reported DNAJB6 pathogenic mutations, localizes in the G/F domain of DNAJB6 protein (Figure B). It also alters an amino acid residue previously reported with a different mutation .…”

“…To date, only 8 different DNAJB6 mutations have been identified in familial or sporadic patients with myopathy in the Caucasian and East Asian populations . These DNAJB6 mutations encompass p.Phe89Ile, p.Phe91Ile, p.Phe91Leu, p.Phe93Ile, p.Phe93Leu, p.Pro96Arg, p.Phe100Val and c.346+5G>A . The majority of the patients with these mutations have limb‐girdle muscular dystrophy type 1D (LGMD1D), characterized by progressive muscle weakness and atrophy predominantly affecting the proximal limbs, whereas a small group of them has distal‐onset myopathy, presenting with muscle weakness and atrophy initiating in the distal lower limbs and propagating to other regions of limbs.…”

“…Serum levels of creatine kinase (CK) in patients with DNAJB6 ‐related myopathy could be normal or up to 10 times of the upper limit of normal ranges and their muscle pathologies generally feature as myopathic changes with rimmed vacuoles and small myofibrillar aggregates . Patients with an advanced disease may have bulbar and cardiopulmonary involvement and lose ambulatory ability …”

“…DNAJB6 contains 3 domains, which are N‐terminal J domain, glycine and phenylalanine‐rich (G/F) domain and C‐terminal domain . All the 8 DNAJB6 mutations identified so far are located within the G/F domain . The G/F domain is essential for DNAJB6 and other similar DnaJ proteins in conformational recognition and substrate binding .…”

Novel mutations in DNAJB6 cause LGMD1D and distal myopathy in French families

“…Autosomal dominant limb girdle muscular dystrophy type 1D (LGMD1D, OMIM 603511) caused by DNAJB6 mutations [1,2] has so far been identified in Europe [1,3,4], Asia [5][6][7][8] and the USA [1,2,9,10]. All reported mutations affect DNAJB6's G/F domain, encoded by exon 5.…”