Calpain 3 gene mutations: genetic and clinico-pathologic findings in limb-girdle muscular dystrophy

Chae, Jong‐Hee; Minami, Narihiro; Jin, Yuko; Nakagawa, Masahiro; Murayama, Kumiko; Igarashi, Fumie; Nonaka, Ikuya

doi:10.1016/s0960-8966(01)00197-3

Cited by 96 publications

(86 citation statements)

References 30 publications

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“…Although this mutation could represent a polymorphism the fact that it was associated with muscle calpain deficiency and was absent in 100 normal Brazilian controls suggests that it is a pathogenic change. In addition this same change in homozygosity was recently reported by Chae et al 17 in Japanese patients.…”

Section: Calpain Mutationssupporting

confidence: 86%

“…Three of them, accounting for 71% of the cases, were recurrent mutations. 17 Although the Brazilian population is highly miscigenated we found two recurrent mutations present in about 46% of our LGMD families: R110X and 2362 -2363EG4TCATCT. Haplotype analysis suggest a common origin for both mutations, suggesting a founder effect.…”

Section: Calpain Mutationsmentioning

confidence: 68%

“…16,17,20 In the present sample, patients from all families in whom both mutations were identified, were classified in three groups according to the nature of the mutation: 18 patients (nine males and nine females) had two missense mutations 16 However the fact that the mean ages of onset and ascertainment did not differ between groups 2 and 3 was unexpected and suggests that one null mutation is enough to determine a more severe phenotype.…”

Section: Mutation Distributionmentioning

confidence: 82%

“…In addition six other mutations were identified exclusively in LGMD2A patients from Japan. 17 However, few genotype phenotype studies, including both DNA as well as protein analysis have been reported to date. Explaining the great inter and intrafamilial clinical variability observed in affected patients remains a great challenge.…”

Section: Introductionmentioning

confidence: 99%

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Clinical variability in calpainopathy: What makes the difference?

et al. 2002

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Limb girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic disorders characterised by progressive weakness of the pelvic and shoulder girdle muscles and a great variability in clinical course.LGMD2A, the most prevalent form of LGMD, is caused by mutations in the calpain-3 gene (CAPN-3). More than 100 pathogenic mutations have been identified to date, however few genotype : phenotype correlation studies, including both DNA and protein analysis, have been reported. In this study we screened 26 unrelated LGMD2A Brazilian families (75 patients) through Single-Stranded Conformation Polymorphism (SSCP), Denaturing high-performance liquid chromatography (DHPLC) and sequencing of abnormal fragments which allowed the identification of 47 mutated alleles (approximately 90%). We identified two recurrent mutations (R110X and 2362-2363AG4TCATCT) and seven novel pathogenic mutations. Interestingly, 41 of the identified mutations (approximately 80%) were concentrated in only 6 exons (1, 2, 4, 5, 11 and 22), which has important implications for diagnostic purposes. Protein analysis, performed in 28 patients from 25 unrelated families showed that with exception of one patient (with normal/slight borderline reduction of calpain) all others had total or partial calpain deficiency. The effects of type of mutation, amount of calpain in the muscle, gender and ethnicity of affected patients on clinical course (age of onset and ascertainment) were analysed. Interestingly, it was observed that, on average, African -Brazilian calpainopathy patients are more severely affected than Caucasians.

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Section: Calpain Mutationssupporting

confidence: 86%

Section: Calpain Mutationsmentioning

confidence: 68%

Section: Mutation Distributionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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Clinical variability in calpainopathy: What makes the difference?

et al. 2002

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“…This variation was identified in several previous reports (Table 1), where its pathogenetic effects have been suggested. 7,32,33 Indeed, because of the lack of a molecular proof, this mutation as well as some intronic variants have been reported either as polymorphisms or as 'possibly pathogenetic' , thus generating confusion and compromising a conclusive genetic counselling. None of these studies have provided a functional effect of the c.1194-9 A4G mutation.…”

Section: Discussionmentioning

confidence: 99%

CAPN3 mRNA processing alteration caused by splicing mutation associated with novel genomic rearrangement of Alu elements

et al. 2011

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Recessive mutations of CAPN3 gene are reported to be responsible for limb girdle muscular dystrophy type 2A (LGMD2A). In all, 15-25% of intronic nucleotide changes identified in this gene were investigated by in silico analysis, but occasionally supported by experimental data or reported in some cases as a polymorphism. We report here genetic and transcriptional analyses in three Tunisian patients belonging to the same consanguineous family sharing the same mutation c.1194-9 A4G and Alu repeats insertion in intron 7 of CAPN3 gene. Reverse transcriptase-PCR experiments performed on total RNA from the patient's muscle biopsy showed retention of the eight last nucleotides of intron 9 in the CAPN3 transcript lacking the first seven exons. Our results provide evidence regarding the potential involvement of Alu elements in aberrant processing of pre-mRNA owing to the disruption of pre-existing intronic splicing regulatory elements. We also demonstrated variable mRNA alternative splicing among tissues and between LGMD2A patients. A deep intronic variation and rearrangement have been reported in the literature as causing genetic diseases in humans. However, this is the first report on a potential pathogenic CAPN3 gene mutation resulting from an Alu insertion.

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Enzymes: Cytosolic Proteins Calpain‐3, SEPN1, and GNE

Straub

Barresi

2013

Muscle Disease

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Calpain 3 gene mutations: genetic and clinico-pathologic findings in limb-girdle muscular dystrophy

Cited by 96 publications

References 30 publications

Clinical variability in calpainopathy: What makes the difference?

Clinical variability in calpainopathy: What makes the difference?

CAPN3 mRNA processing alteration caused by splicing mutation associated with novel genomic rearrangement of Alu elements

Enzymes: Cytosolic Proteins Calpain‐3, SEPN1, and GNE

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