Calpain III mutation analysis of a heterogeneous limb–girdle muscular dystrophy population

Chou, F. L.; Angelini, C.; Daentl, Donna L.; García, Carlos; Greco, Carolina; Hausmanowa-Pétrusewicz, I; Fidziańska, Anna; Wessel, Henry B.; Hoffman, Eric P.

doi:10.1212/wnl.52.5.1015

Cited by 54 publications

(26 citation statements)

References 30 publications

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“…The classic presentation of the symptoms has been the weakness of the hip-girdle muscles, but can also present as involvement of the shoulder girdle or lower-limb distal muscles, muscular pain, and exercise intolerance 20,36,37 . Some specific patterns can be observed in the calpainopathy (LGMD2A), by involvement of posterior limb-girdle and trunk muscles; in the dysferlinopathy (LGMD2B), by involvement of the posterior compartment of the legs 33,38,39 ; in the telethoninopathy (LGMD2G) and titinopathy (LGMD2J), by involvement of the anterior compartment of leg 22,34 .…”

Section: Discussionmentioning

confidence: 99%

Limb-girdle muscular dystrophy: an immunohistochemical diagnostic approach

Comerlato

Scola

Werneck

2005

Arq. Neuro-Psiquiatr.

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The limb-girdle muscle dystrophy (LGMD) represents a heterogeneous group of muscular diseases with dominant and recessive inheritance, individualized by gene mutation. A group of 56 patients, 32 males and 24 females, with suggestive LGMD diagnosis were submitted to clinical evaluation, serum muscle enzymes, electromyography, muscle biopsy, and the immunoidentification (ID) of sarcoglycans (SG) alpha, beta, gamma and delta, dysferlin and western blot for calpain-3. All the patients had normal ID for dystrophin (rod domain, carboxyl and amine terminal). The alpha-SG was normal in 42 patients, beta-SG in 28, beta-SG in 45, delta-SG in 32, dysferlin in 37 and calpain-3 in 9. There was a reduction in the alpha-SG in 7 patients, beta-SG in 4, gamma-SG in 2, and delta-SG in 8. There was deficiency of alpha-SG in 7 patients, beta-SG in 6, gamma-SG in 9, delta-SG in 5, dysferlin in 8, and calpain-3 in 5. The patients were grouped according the ID as sarcoglycans deficiency 18 cases, dysferlin deficiency 8 cases and calpain-3 deficiency 5 cases. Only the sarcoglycans deficiency group showed calf hypertrophy. The dysferlin deficiency group was more frequent in females and the onset was later than sarcoglycan and calpain-3 deficiency groups. The calpain-3 deficiency group occurred only in males and showed an earlier onset and weaker muscular strength.

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Section: Discussionmentioning

confidence: 99%

Limb-girdle muscular dystrophy: an immunohistochemical diagnostic approach

Comerlato

Scola

Werneck

2005

Arq. Neuro-Psiquiatr.

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“…Estimates based on molecular data indicate that LGMD2A frequency ranges from about 10% of LGMD cases in the United States 18,19 to 80% in the Basque country and Russia. 16,20 LGMD2A is caused by mutations in the CAPN3 gene (MIM#114240, mapped to 15q15.1 -q21.1) encoding for a muscle-specific proteolytic enzyme called calpain-3 21 that is involved in the complex process of sarcomere remodeling.…”

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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“…2 More than 110 different CAPN-3 gene mutations have been described [3][4][5][6][7][8][9][10] ; about 45% are null mutations and half are missense.…”

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confidence: 99%

Loss of Calpain-3 Autocatalytic Activity in LGMD2A Patients with Normal Protein Expression

Fanin

Nascimbeni

Fulizio

et al. 2003

The American Journal of Pathology

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The diagnosis of limb girdle muscular dystrophy (LGMD) type 2A (due to mutations in the gene encoding for calpain-3) is currently based on protein analysis, but mutant patients with normal protein expression have also been identified. In this study we investigated 150 LGMD patients with normal calpain-3 protein expression, identified gene mutations by an allele-specific polymerase chain reaction test, and analyzed the mutant calpain-3 catalytic activity. Four different mutations were found in eight patients (5.5%): a frame-shifting deletion (550 A del) and three missense (R490Q, R489Q, R490W). Patients with normal calpain-3 protein expression on Western blot are a considerable proportion (20%) of our total LGMD2A population. While in control muscle the calpain-3 Ca ؉؉ -dependent autocatalytic activity was evident within 5 minutes and was prevented by ethylene diaminetetraacetic acid, in all mutant patient samples the protein was not degraded, indicating that the normal autocatalytic function had been lost. By this new functional test, we show that conventional protein diagnosis fails to detect some mutant proteins, and prove the pathogenetic role of R490Q, R489Q, R490W missense mutations. We suggest that these mutations impair protein activity by affecting interdomain protein interaction, or reduce autocatalytic activity by lowering the Ca

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Calpain III mutation analysis of a heterogeneous limb–girdle muscular dystrophy population

Cited by 54 publications

References 30 publications

Limb-girdle muscular dystrophy: an immunohistochemical diagnostic approach

Limb-girdle muscular dystrophy: an immunohistochemical diagnostic approach

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

Loss of Calpain-3 Autocatalytic Activity in LGMD2A Patients with Normal Protein Expression

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