Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy
Introduction
Autosomal dominant limb-girdle muscular dystrophies (LGMD1) are a genetically and clinically heterogeneous group of disorders. LGMD1 often presents with progressive proximal muscle weakness of the upper and lower extremities; however several forms may present with primarily distal weakness, and clinical heterogeneity may exist even within the same family [1]. To date, mutations in five causative genes have been associated with LGMD1, including the MYOT gene encoding myotilin in LGMD1A [2], the LMNA gene encoding lamin A/C in LGMD1B [3], the CAV3 gene which encodes caveolin in LGMD1C [4]. More recently, mutations in the DNAJB6 gene have been described in LGMD1D patients [5], [6], [7] and mutations in Transportin 3 (TNPO3) gene have been linked to LGMD1F [8], [9]. Additional loci linked to LGMD1 have been mapped, but causative genes have not been identified [1].
Using exome sequencing, we sought to determine the genetic basis for LGMD1 in an American family of Northern European descent that presented with an autosomal dominant pattern of inheritance. Exome sequencing has been used to great effect to identify the underlying mutations in a number of diseases, including recently in LGMD1 [5], [8].
Section snippets
Patients and methods
All aspects of this study were approved by the Stanford University Institutional Review Board and written informed consent was received.
Proband (III-3, Fig. 1A arrowhead) presented at 55 years of age to clinic, with a history of slow running and difficulty climbing stairs, beginning shortly after high school. He began using a cane in his late 30s, two canes in his 40s, and at 56 years of age, developed acute worsening of upper and lower extremity strength owing to severe cervical spinal cord
Exome sequencing
Exome sequencing was performed for two affected brothers (Fig. 1A red asterisks; III-1 and III-3) and one unaffected sister (III-2); average coverage depth was 60X. Eleven novel variants shared between the two affected brothers (III-1 and III-3) but not present in the unaffected sister (III-2) were identified (Supplemental Table 1). Included in the list of disease-segregating variants was a variation in the DNAJB6 gene, c.265T > A, producing a p.Phe89Ile substitution, which is located in the G/F
Discussion
Using the unbiased technique of exome sequencing, we identified a mutation in DNAJB6 in a family with LGMD1. LGMD1D was originally described in several Finnish families with linkage to chromosome 7q36 and recently three studies in Finnish, Italian, American, and Japanese families revealed the causative gene to be DNAJB6 [5], [6], [7], [15], [18]. The nomenclature of LGMD associated with DNAJB6 mutations is confusing, with some groups utilizing the HUGO Gene Nomenclature Committee’s locus
Acknowledgements
We thank the patients and their family for participating in this study. Supported by NIH Director’s New Innovator Award DP2OD004417 (A.D.G.), NIH Grants NS065317 (A.D.G.) and NS073660 (A.D.G.). A.D.G. is a Pew Scholar in the Biomedical Sciences, supported by The Pew Charitable Trusts, and a Rita Allen Foundation Scholar. A.R.R. is supported by an Alzheimer’s Disease Research Grant from the BrightFocus Foundation. J.D.B. is supported by the NIH-NHGRI Stanford Genome Science training grant. We
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Distal myopathy
2023, Handbook of Clinical NeurologyDNAJB6, a Key Factor in Neuronal Sensitivity to Amyloidogenesis
2020, Molecular CellIntrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type
2020, European Journal of Medical GeneticsCitation Excerpt :The previously reported variants affecting the Phe91 residue (Supplementary Table 3) include c.271T > A p.(Phe91Ile); c.271T > C p.(Phe91Leu), and c.273C > G p.(Phe91Leu) (Palmio et al., 2015; Ruggieri et al., 2015; Nam et al., 2015; Jonson et al., 2018). These patients from multiple families have an earlier onset of symptoms in childhood or adolescence, atypical for LGMD1D, and have a particularly severe phenotype that commonly includes respiratory and bulbar involvement (Couthouis et al., 2014; Nam et al., 2015; Palmio et al., 2015; Ruggieri et al., 2015). However, the c.271T > G (p.Phe91Val) variant reported here causes a much milder phenotype in our Hungarian family, with symptoms first reported in the third and fourth decade of life in two individuals and another female individual being clinically asymptomatic in her early 60s.
Hypo- and Hyper-Assembly Diseases of RNA–Protein Complexes
2016, Trends in Molecular MedicineA novel mutation in DNAJB6, p.(Phe91Leu), in childhood-onset LGMD1D with a severe phenotype
2015, Neuromuscular DisordersCitation Excerpt :Muscle defects were more severe in embryos injected with p.Phe89Ile or p.Phe91Leu as compared to those injected with p.Phe93Leu or p.Pro96Arg (Fig. 4A and B and Fig. S1). This outcome appears to reflect phenotypes of LGMD1D patients with corresponding mutations, in that childhood-onset LGMD1D was also reported for p.Phe89Ile, but not for p.Phe93Leu or p.Pro96Arg patients [12,13,22]. Here, we show that a novel p.(Phe91Leu) mutation in the DNAJB6 of a Korean family is implicated in LGMD1D.
Novel mutations in DNAJB6 gene cause a very severe early-onset limb-girdle muscular dystrophy 1D disease
2015, Neuromuscular DisordersCitation Excerpt :The original p.F93L and p.F89I mutations are in this setup not significantly changed from wild-type b and wild-type a, respectively. The previously reported mutations in DNAJB6 are known to cause adult-onset LGMD1D with mild to moderate progression and without respiratory muscle involvement [4–8]. 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.
- 1
These authors contributed equally to the manuscript.
- 2
Current address: University of California Irvine School of Medicine, Irvine, CA, USA.