Calpain-3 mutations in Turkey

Balcı, Burcu; Aurino, S.; Haliloğlu, Göknur; Talim, Beril; Erdem, Sevim; Akçören, Zühal; Tan, Ersin; Richard, Isabelle; Nigro, Vincenzo; Topaloǧlu, Haluk; Dinçer, Pervin

doi:10.1007/s00431-005-0046-3

Cited by 33 publications

(18 citation statements)

References 29 publications

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“…This relatively high proportion of cases can partly be attributed to the recurrence of the R490Q mutation in a population from northeastern Italy. 22 However, the R490Q mutation is the second most frequent mutant allele in patients with LGMD2A from Turkey, 23 and it has also been reported in other countries according to the Leiden Muscular Dystrophy database; furthermore, even if we exclude the five cases with homozygotic R490Q mutation, the proportion of mutant patients with loss of autolytic function remains high (12.3%) and probably reflects the real estimate in populations where there are no genetic isolates. Such cases would probably not have been diagnosed following the finding of normal protein quantity on conventional immunoblotting, unless there also was thorough CAPN3 gene mutation screening which, however, is currently available only on a research basis.…”

Section: Discussionmentioning

confidence: 77%

Screening of calpain-3 autolytic activity in LGMD muscle: a functional map of CAPN3 gene mutations

Fanin

Nascimbeni

Angelini

2006

Journal of Medical Genetics

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Background: The diagnosis of calpainopathy is obtained by identifying calpain-3 protein deficiency or CAPN3 gene mutations. However, in many patients with limb girdle muscular dystrophy type 2A (LGMD2A), the calpain-3 protein quantity is normal because loss-of-function mutations cause its enzymatic inactivation. The identification of such patients is difficult unless a functional test suggests pursuing a search for mutations. Materials and methods: A functional in vitro assay, which was able to test calpain-3 autolytic function, was used to screen a large series of muscle biopsy specimens from patients with unclassified LGMD/ hyperCKaemia who have previously shown normal calpain-3 protein quantity. Results: Of 148 muscle biopsy specimens tested,17 samples (11%) had lost normal autolytic function. CAPN3 gene mutations were identified in 15 of 17 patients (88%), who account for about 20% of the total patients with LGMD2A diagnosed in our series. Conclusions:The loss of calpain-3 autolytic activity is highly predictive of primary calpainopathy, and the use of this test as part of calpainopathy diagnosis would improve the rate of disease detection markedly. This study provides the first evidence of the pathogenetic effect of specific CAPN3 gene mutations on the corresponding protein function in LGMD2A muscle and offers new insights into the structural-functional relationship of the gene and protein regions that are crucial for the autolytic activity of calpain-3.

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Section: Discussionmentioning

confidence: 77%

Screening of calpain-3 autolytic activity in LGMD muscle: a functional map of CAPN3 gene mutations

Fanin

Nascimbeni

Angelini

2006

Journal of Medical Genetics

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“…c.550delA mutation is the most common allele in Caucasian populations. [30] Founder effect for the c.550delA mutation has been demonstrated in the Eastern Mediterranean region (Russia, Croatia, Bulgaria, and Northern Italy)[313233343536373839404142] Other rare mutations which have a founder effect in small populations due to cultural inbreeding associated with historical, demographic, or religious factors have been reported in the population of La Reunion Island in the Indian Ocean (c.946-1G>A),[43] in the Old Order Amish community in Northern Indiana in the USA (c.2306G>A),[4445] in the Guipuzcoa region of the Basque Country of Spain and in Brazil (c.2362_2363delAGinsTCATCT),[464748] Japan (c.1795_1796insA),[495051] the Chioggia village in the Venetian lagoon (p.R490Q),[35] the Mocheni population in the Italian Alps (c.1193 + 6T>A),[52] and the Agarwal community in Northern India (p.D780H and c.2099-1G>T). [53] The last one is relevant to India and hence is discussed further.…”

Section: Calpainopathymentioning

confidence: 99%

Limb-girdle muscular dystrophies in India: A review

Khadilkar¹,

Faldu²,

Patil³

et al. 2017

Ann Indian Acad Neurol

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Limb-girdle muscular dystrophies (LGMDs) are common in India. Information on LGMDs has been gradually evolving in the recent years. This information is scattered in case series and case studies. The aim of this study is to collate available Indian information on LGMDs and put it in perspective. PubMed search using keywords such as limb-girdle muscular dystrophies in India, sarcoglycanopathies, dysferlinopathy, calpainopathy, and GNE myopathy was carried out. The published information on LGMDs in Indian context suggests that dysferlinopathy, calpainopathy, sarcoglycanopathies, and other myopathies such as GNE myopathy are frequently seen in India. Besides these, anecdotal reports of many other forms are available, some with genetic support and others showing immunocytochemical defects. The genotypic information on LGMDs is gradually evolving and founder mutations have been detected in selected populations. Further multicenter studies are necessary to document the incidence and prevalence of these common conditions in India.

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“…Although LGMD2I is the most common form of all LGMDs in Northern Europe, 1 LGMD2A (MIM#253600) is the most prevalent in many European countries, 2 -10 Turkey, 11,12 Brazil, 13 Japan, 14,15 Russia 16 and Australia, 17 with variable frequencies that differ depending on ethnic clusters and geographic origins. 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.…”

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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Calpain-3 mutations in Turkey

Cited by 33 publications

References 29 publications

Screening of calpain-3 autolytic activity in LGMD muscle: a functional map of CAPN3 gene mutations

Screening of calpain-3 autolytic activity in LGMD muscle: a functional map of CAPN3 gene mutations

Limb-girdle muscular dystrophies in India: A review

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

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