Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy

Abstract

Limb-girdle muscular dystrophy primarily affects the muscles of the hips and shoulders (the “limb-girdle” muscles), although it is a heterogeneous disorder that can present with varying symptoms; there is currently no cure. We sought to identify the genetic basis of limb-girdle muscular dystrophy type 1 in an American family of Northern European descent using exome sequencing. Exome sequencing was performed on DNA samples from two affected siblings and one unaffected sibling and resulted in the identification of eleven candidate mutations that co-segregated with the disease. Notably, this list included a previously reported mutation in DNAJB6, p.Phe89Ile, which was recently identified as a cause of limb-girdle muscular dystrophy type 1D. Additional family members were Sanger sequenced and the mutation in DNAJB6 was only found in affected individuals. Subsequent haplotype analysis indicated that this DNAJB6 p.Phe89Ile mutation likely arose independently of the previously reported mutation. Since other published mutations are located close by in the G/F domain of DNAJB6, this suggests that the area may represent a mutational hotspot. Exome sequencing provided an unbiased and effective method for identifying the genetic etiology of limb-girdle muscular dystrophy type 1 in a previously genetically uncharacterized family. This work further confirms the causative role of DNAJB6 mutations in limb-girdle muscular dystrophy type 1D.

Novel mutations in DNAJB6 gene cause a very severe early-onset limb-girdle muscular dystrophy 1D disease

“…The previously reported mutations in DNAJB6 are known to cause adult-onset LGMD1D with mild to moderate progression and without respiratory muscle involvement [4][5][6][7][8]. The two novel mutations in DNAJB6 reported here, however, cause severe childhood-onset disease with reduced walking, contractures and progressive respiratory insufficiency with a loss of ambulation in early adulthood.…”

“…Only one patient, out of approximately 100, had dyspnea and sleep-associated breathing disorder with reduced FVC in mid-adulthood [7]. The two mutations in our patients caused marked respiratory problems already in early adulthood with important clinical relevance.…”

“…DNAJB6 belongs to a class of co-chaperones characterized by a J-domain in the N-terminus [5]. All four reported disease-causing coding mutations, p.F89I, p.F93I, p.F93L, and p.P96R, are located in the G/F-rich linker domain of DNAJB6 [4][5][6][7][8]. The previously reported mutations usually cause adult-onset, slowly progressive proximal muscle weakness.…”

“…The previously reported mutations usually cause adult-onset, slowly progressive proximal muscle weakness. However, occasional patients with earlier onset have been reported, although in these patients the further evolution was moderate with loss of ambulation only after age 50 and without respiratory failure [7,8].…”

Myopathy-causing Mutations in an HSP40 Chaperone Disrupt Processing of Specific Client Conformers

“…Dominantly inherited mutations in the HSP40 chaperone DNAJB6 cause a progressive, late-onset degenerative myopathy called limb-girdle muscular dystrophy type 1D (LGMD1D) (1)(2)(3)(4). DNAJB6 is expressed as two isoforms, DNAJB6a and DNAJB6b, with DNAJB6b suggested to be the principal mediator of LGMD1D pathogenesis (2).…”