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A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy

Lookup NU author(s): Dr Rita Barresi, Professor Volker StraubORCiD, Professor Hanns Lochmuller


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Limb girdle muscular dystrophy type 2A is the most common limb girdle muscular dystrophy form worldwide. Although strict recessive inheritance is assumed, patients carrying a single mutation in the calpain 3 gene (CAPN3) are reported. Such findings are commonly attributed to incomplete mutation screening. In this investigation, we report 37 individuals (age range: 21-85 years, 21 females and 16 males) from 10 families in whom only one mutation in CAPN3 could be identified; a 21-bp, in-frame deletion (c.643_663del21). This mutation co-segregated with evidence of muscle disease and autosomal dominant transmission in several generations. Evidence of muscle disease was indicated by muscle pain, muscle weakness and wasting, significant fat replacement of muscles on imaging, myopathic changes on muscle biopsy and loss of calpain 3 protein on western blotting. Thirty-one of 34 patients had elevated creatine kinase or myoglobin. Muscle weakness was generally milder than observed in limb girdle muscular dystrophy type 2A, but affected the same muscle groups (proximal leg, lumbar paraspinal and medial gastrocnemius muscles). In some cases, the weakness was severely disabling. The 21-bp deletion did not affect mRNA maturation. Calpain 3 expression in muscle, assessed by western blot, was below 15% of normal levels in the nine mutation carriers in whom this could be tested. Haplotype analysis in four families from three different countries suggests that the 21-bp deletion is a founder mutation. This study provides strong evidence that heterozygosity for the c.643_63del21 deletion in CAPN3 results in a dominantly inherited muscle disease. The normal expression of mutated mRNA and the severe loss of calpain 3 on western blotting, suggest a dominant negative effect with a loss-of-function mechanism affecting the calpain 3 homodimer. This renders patients deficient in calpain 3 as in limb girdle muscular dystrophy type 2A, albeit in a milder form in most cases. Based on findings in 10 families, our study indicates that a dominantly inherited pattern of calpainopathy exists, and should be considered in the diagnostic work-up and genetic counselling of patients with calpainopathy and single-allele aberrations in CAPN3.

Publication metadata

Author(s): Vissing J, Barresi R, Witting N, Van Ghelue M, Gammelgaard L, Bindoff LA, Straub V, Lochm├╝ller H, Hudson J, Wahl CM, Arnardottir S, Dahlbom K, Jonsrud C, Duno M

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2016

Volume: 139

Issue: 8

Pages: 2154-2163

Print publication date: 01/08/2016

Online publication date: 03/06/2016

Acceptance date: 30/04/2016

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press


DOI: 10.1093/brain/aww133

PubMed id: 27259757


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Funder referenceFunder name
98482Medical Research Council UK
305121European Union
305444European Union
G1002274Medical Research Council UK