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

John Vissing; Rita Barresi; Nanna Witting; Marijke Van Ghelue; Lise Gammelgaard; Laurence A Bindoff; Volker Straub; Hanns Lochmüller; Judith Hudson; Snjolaug Arnardottir; Kathe Dahlbom; Christoffer Jonsrud; Morten Duno

doi:10.1093/brain/aww133

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

John Vissing, Rita Barresi, Nanna Witting, Marijke Van Ghelue, Lise Gammelgaard, Laurence A Bindoff, Volker Straub, Hanns Lochmüller, Judith Hudson, Snjolaug Arnardottir, Kathe Dahlbom, Christoffer Jonsrud, Morten Duno

Institut for Klinisk Medicin

46 Citationer (Scopus)

Abstract

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_663del21 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.

Originalsprog	Engelsk
Tidsskrift	Brain
Vol/bind	139
Udgave nummer	8
Sider (fra-til)	2154-2163
Antal sider	10
ISSN	0006-8950
DOI	https://doi.org/10.1093/brain/aww133
Status	Udgivet - 1 aug. 2016

Adgang til dokumentet

10.1093/brain/aww133

aww133.pdfForlagets udgivne version, 649 KB

https://academic.oup.com/brain/article-pdf/139/8/2154/17944649/aww133.pdf

Citationsformater

@article{fe3a6d4893814435bf9cb30cf24bd212,

title = "A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy",

abstract = "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_663del21 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.",

keywords = "Journal Article",

author = "John Vissing and Rita Barresi and Nanna Witting and {Van Ghelue}, Marijke and Lise Gammelgaard and Bindoff, {Laurence A} and Volker Straub and Hanns Lochm{\"u}ller and Judith Hudson and Snjolaug Arnardottir and Kathe Dahlbom and Christoffer Jonsrud and Morten Duno",

year = "2016",

month = aug,

day = "1",

doi = "10.1093/brain/aww133",

language = "English",

volume = "139",

pages = "2154--2163",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "8",

}

TY - JOUR

T1 - A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy

AU - Vissing, John

AU - Barresi, Rita

AU - Witting, Nanna

AU - Van Ghelue, Marijke

AU - Gammelgaard, Lise

AU - Bindoff, Laurence A

AU - Straub, Volker

AU - Lochmüller, Hanns

AU - Hudson, Judith

AU - Arnardottir, Snjolaug

AU - Dahlbom, Kathe

AU - Jonsrud, Christoffer

AU - Duno, Morten

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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_663del21 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.

AB - 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_663del21 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.

KW - Journal Article

U2 - 10.1093/brain/aww133

DO - 10.1093/brain/aww133

M3 - Journal article

C2 - 27259757

SN - 0006-8950

VL - 139

SP - 2154

EP - 2163

JO - Brain

JF - Brain

IS - 8

ER -

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

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater