Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes

Piluso, Giulio; Politano, Luisa; Aurino, S.; Fanin, Marina; Ricci, Enzo; Ventriglia, V.M.; Belsito, Angela; Totaro, Angela; Saccone, Valentina; Topaloǧlu, Haluk; Nascimbeni, Anna Chiara; Fulizio, Luigi; Broccolini, Aldobrando; Canki-Klain, Nina; Comi, L.I.; Nigro, Gerardo; Angelini, C.; Nigro, Vincenzo

doi:10.1136/jmg.2004.028738

Cited by 96 publications

(76 citation statements)

References 47 publications

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“…Interestingly, previous reports had indicated an early onset in men rather than in women, difference relative to wheelchair dependent patients between genders or a more rapid progression in men 23, 31, 32. Interestingly, a difference in fiber atrophy between genders has recently been reported in LGMD,33 a fact which may support of this dissimilarity.…”

Section: Discussionmentioning

confidence: 86%

Natural history of LGMD2A for delineating outcome measures in clinical trials

Richard

Hogrel

Stockholm

et al. 2016

Ann Clin Transl Neurol

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ObjectiveLimb‐girdle muscular dystophy 2A (LGMD2A, OMIM) is a slowly progressive myopathy caused by the deficiency in calpain 3, a calcium‐dependent cysteine protease of the skeletal muscle.MethodsIn this study, we carried out an observational study of clinical manifestations and disease progression in genetically confirmed LGMD2A patients for up to 4 years. A total of 85 patients, aged 14–65 years, were recruited in three centers located in metropolitan France, the Basque country, and the Reunion Island. They were followed up every 6 months for 2 years and a subgroup was assessed annually thereafter for two more years. Data collected for all patients included clinical history, blood parameters, muscle strength assessed by manual muscle testing (MMT) and quantitative muscle testing, functional scores, and pulmonary and cardiac functions. In addition, CT scans of the lower limbs were performed in a subgroup of patients.ResultsOur study confirms the clinical description of a slowly progressive disorder with onset in the first or second decade of life with some degree of variability related to gender and mutation type. The null mutations lead to a more severe phenotype while compound heterozygote patients are the least affected. Muscle weakness is remarkably symmetrical and predominant in the axial muscles of the trunk and proximal muscles of the lower limb. There was a high correlation between the weakness at individual muscle level as assessed by MMT and the loss of density in CT scan analysis.InterpretationAll the generated data will help to determine the endpoints for further clinical studies.

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Section: Discussionmentioning

confidence: 86%

Natural history of LGMD2A for delineating outcome measures in clinical trials

Richard

Hogrel

Stockholm

et al. 2016

Ann Clin Transl Neurol

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“…23 -26 The onset of muscle weakness and the progress of clinical course may vary considerably, as may the spectrum of phenotypes that is becoming increasingly wider, including, hyperCKemia, pseudometabolic myopathy and eosinophilic myositis. 5,27,28 Genotype -phenotype correlation studies have demonstrated that this clinical variability may be only partly attributable to gene mutations 24,26,29,30 (interfamilial and intrafamilial variability because of the same mutation), which suggests that additional epigenetic/environmental factors might play a role in modulating the phenotype expression. The molecular diagnosis of LGMD2A is increasingly being demanded because of the high frequency of the disease.…”

Section: Introductionmentioning

confidence: 99%

How to tackle the diagnosis of limb-girdle muscular dystrophy 2A

et al. 2008

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Limb-girdle muscular dystrophy (LGMD) 2A (calpainopathy) is the most frequent form of LGMD in many European countries. The increasing demand for a molecular diagnosis makes the identification of strategies to improve gene mutation detection crucial. We conducted both a quantitative analysis of calpain-3 protein in 519 muscles from patients with unclassified LGMD, unclassified myopathy and hyperCKemia, and a functional assay of calpain-3 autolytic activity in 108 cases with LGMD and normal protein quantity. Subsequently, screening of CAPN3 gene mutations was performed using allele-specific tests and simplified SSCP analysis. We diagnosed a total of 94 LGMD2A patients, carrying 66 different mutations (six are newly identified). The probability of diagnosing calpainopathy was very high in patients showing either a quantitative (80%) or a functional calpain-3 protein defect (88%). Our data show a high predictive value for reduced-absent calpain-3 or lost autolytic activity. These biochemical assays are powerful tools for otherwise laborious genetic screening of cases with a high probability of being primary calpainopathy. Our multistep diagnostic approach is rational and highly effective. This strategy has improved the detection rate of the disease and our extension of screening to presymptomatic phenotypes (hyperCKemia) has allowed us to obtain early diagnoses, which has important consequences for patient care and genetic counseling.

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“…These transcripts are variably expressed and not always detectable in the mutant patients. 15,18,36 In our study, it seems reasonable to deduce that the observed variability between two siblings sharing the same mutation is owing to the ability to splice the mutant allele. The clinical heterogeneity observed in this family supported findings of previous studies concerning CAPN3-splicing mutations (Table 1).…”

Section: Intronic Alterations Affect Splicing Of Capn3 Genementioning

confidence: 96%

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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Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes

Cited by 96 publications

References 47 publications

Natural history of LGMD2A for delineating outcome measures in clinical trials

Natural history of LGMD2A for delineating outcome measures in clinical trials

How to tackle the diagnosis of limb-girdle muscular dystrophy 2A

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

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