Prevalence of the 550delA mutation in calpainopathy (LGMD 2A) in Croatia

Canki-Klain, Nina; Milić, Astrid; Kovač, Biserka; Trlaja, Anuška; Grgicević, D; Zurak, Niko; Fardeau, Michel; Kaplan, Jean‐Claude; Urtizberea, J. Andoni; Politano, Luisa; Piluso, Giulio; Feingold, Josué

doi:10.1002/ajmg.a.20408

Cited by 32 publications

(21 citation statements)

References 15 publications

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“…This mutation has been suggested to originate in the eastern Mediterranean region, from which it has probably been spread widely across Europe. 4,17 Although there is a marked inter-and intrafamilial heterogeneity in the clinical course of LGMD2A patients, it has been suggested repeatedly that missense mutations are usually associated with a milder phenotype than null mutations. 5,7,21 Five patients (1, 7-9, and 13) carried null mutations on both alleles of the CAPN3 gene, which corresponds with the early onset of clinical symptoms (mean age at onset was 7.6 years, range 4 -10 years).…”

Section: Discussionmentioning

confidence: 99%

Analysis of histopathologic and molecular pathologic findings in Czech LGMD2A patients

et al. 2005

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Limb-girdle muscular dystrophy type 2A (LGMD2A) is an autosomal-recessive disorder characterized by selective atrophy and progressive weakness of proximal girdle muscles. LGMD2A, the most prevalent form of LGMD, is caused by mutations in the CAPN3 gene that encodes the skeletal muscle-specific member of the calpain family, calpain-3 (p 94). We examined the histopathologic and molecular pathologic findings in 14 Czech LGMD2A patients. Analysis of the CAPN3 gene was performed at the mRNA level, using reverse transcription-polymerase chain reaction (RT-PCR) and sequencing, and/or DNA level, using PCR and denaturing high-performance liquid chromatography (DHPLC). Our results confirm that mutation 550 delA is the most frequent CAPN3 defect in Czech LGMD2A patients (9 alleles of 28). Furthermore, we established that, in a patient with the 550 delA/R490W genotype, mRNA carrying frameshift mutation 550 delA was not detected, probably due to its degradation by nonsense-mediated mRNA decay. In muscle biopsies of two LGMD2A patients, a neurogenic pattern simulating a neurogenic lesion was observed. Immunoblot analysis revealed the deficiency of p 94 in all genetically confirmed cases of LGMD2A, and secondary dysferlin deficiency was demonstrated on muscle membranes in 6 patients using immunofluorescence. Thus, we find a combination of DNA and mRNA mutational analysis to be useful in the diagnosis of LGMD2A. Moreover, our study expands the spectrum of calpainopathies to cases that simulate a neurogenic lesion in muscle biopsies, and the knowledge of possible secondary deficiencies of muscular proteins also contributes to a diagnosis of LGMD2A.

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Section: Discussionmentioning

confidence: 99%

Analysis of histopathologic and molecular pathologic findings in Czech LGMD2A patients

et al. 2005

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“…The positions of the mutation found in the LGMd2A patients were distributed widely within CAPN3, with more than half the mutations being missense [19,24,33,131,132,135,137]. No "hot point" was found, making diagnosis of the disease very difficult.…”

Section: Skeletal Muscle-specific Calpain Calpain-3/p94mentioning

confidence: 99%

Expanding Members and Roles of the Calpain Superfamily and Their Genetically Modified Animals

2010

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Abstract:Calpains are intracellular Ca 2+ -dependent cysteine proteases (Clan CA, family C02, EC 3.4.22.17) found in almost all eukaryotes and some bacteria. Calpains display limited proteolytic activity at neutral pH, proteolysing substrates to transform and modulate their structures and activities, and are therefore called "modulator proteases". The human genome has 15 genes that encode a calpain-like protease domain, generating diverse calpain homologues that possess combinations of several functional domains such as Ca 2+ -binding domains and Zn-finger domains. The importance of the physiological roles of calpains is reflected in the fact that particular defects in calpain functionality cause a variety of deficiencies in many different organisms, including lethality, muscular dystrophies, lissencephaly, and tumorigenesis. In this review, the unique characteristics of this distinctive protease superfamily are introduced in terms of genetically modified animals, some of which are animal models of calpain deficiency diseases.

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“…PCR reactions were performed as described elsewhere. 8 LGMD 0 F c.1333G4A, p.G445R, ex.10 F Fanin et al 26 …”

Section: Analysis Of Calpain-3 Autolytic Activitymentioning

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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Prevalence of the 550delA mutation in calpainopathy (LGMD 2A) in Croatia

Cited by 32 publications

References 15 publications

Analysis of histopathologic and molecular pathologic findings in Czech LGMD2A patients

Analysis of histopathologic and molecular pathologic findings in Czech LGMD2A patients

Expanding Members and Roles of the Calpain Superfamily and Their Genetically Modified Animals

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

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