Clinical, pathological, and genetic features of limb-girdle muscular dystrophy type 2A with new calpain 3 gene mutations in seven patients from three Japanese families

Kawai, Hisaomi; Akiyama, Masashi; Kunishige, Makoto; Inui, Toshio; Adachi, Kazutaka; Kimura, Chiyomi; Kawajiri, Masakazu; Nishida, Yoshihiko; Endo, Itsuro; Kashiwagi, Setsuko; Nishino, Hiroshi; Fujiwara, Tsutomu; Okuno, Shiro; Roudaut, Carinne; Richard, Isabelle; Beckmann, Jacques S.; Miyoshi, Kazuo; Matsumoto, Toshio

doi:10.1002/(sici)1097-4598(199811)21:11<1493::aid-mus19>3.0.co;2-1

Cited by 42 publications

(22 citation statements)

References 34 publications

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“…6,7 In this condition, diminished muscle calpain activity results in progressive weakness in the proximal limb-girdle muscles. Skeletal muscle biopsies of LGMD2A patients show variable skeletal myofiber size, myofiber atrophy, and patchy dystrophin staining, 33,34 which resemble the histological findings in our cardiac calpain inhibition model, calpastatin overexpression. More recently, a role for calpain 3 in skeletal muscle ubiquitination and proteasomal degradation has also been suggested.…”

Section: Discussionmentioning

confidence: 85%

“…In approximately half of the calpastatin mice, atrial arrhythmias occurred (supplemental Figure III). Histological examination of calpastatin-overexpressing myocardium showed features similar to skeletal muscle biopsies in patients with LGMD2A, including variability of myocyte size (Figure 4a and 4e), frequent intracellular inclusions (Figure 4a, top), and distorted myofibrillar architecture with regionally abnormal or absent staining for sarcolemmal dystrophin 33,34 (Figure 4a, middle). Mean cardiomyocyte crosssectional area was 332Ϯ11 m 2 in calpastatin versus 252Ϯ22 m 2 in NTG (nϭ500 to 600 cells from each of 3 pairs of hearts, PϽ0.05).…”

Section: Cardiac Calpainopathy With Calpastatin Overexpressionmentioning

confidence: 99%

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Cardiomyocyte Degeneration With Calpain Deficiency Reveals a Critical Role in Protein Homeostasis

Gálvez

Diwan

Odley

et al. 2007

Circulation Research

125

110

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Abstract-Regulating the balance between synthesis and proteasomal degradation of cellular proteins is essential for tissue growth and maintenance, but the critical pathways regulating protein ubiquitination and degradation are incompletely defined. Although participation of calpain calcium-activated proteases in post-necrotic myocardial autolysis is well characterized, their importance in homeostatic turnover of normal cardiac tissue is controversial. Hence, we evaluated the consequences of physiologic calpain (calcium-activated protease) activity in cultured cardiomyocytes and unstressed mouse hearts. Comparison of in vitro proteolytic activities of cardiac-expressed calpains 1 and 2 revealed calpain 1, but not calpain 2, activity at physiological calcium concentrations. Physiological calpain 1 activation was evident in adenoviral transfected cultured cardiomyocytes as proteolysis of specific substrates, generally increased protein ubiquitination, and accelerated protein turnover, that were each inhibited by coexpression of the inhibitor protein calpastatin. Conditional forced expression of calpain 1, but not calpain 2, in mouse hearts demonstrated substratespecific proteolytic activity under basal conditions, with hyperubiquitination of cardiac proteins and increased 26S proteasome activity. Loss of myocardial calpain activity by forced expression of calpastatin diminished ubiquitination of 1 or more specific myocardial proteins, without affecting overall ubiquitination or proteasome activity, and resulted in a progressive dilated cardiomyopathy characterized by accumulation of intracellular protein aggregates, formation of autophagosomes, and degeneration of sarcomeres. Thus, calpain 1 is upstream of, and necessary for, ubiquitination and proteasomal degradation of a subset of myocardial proteins whose abnormal accumulation produces autophagosomes and degeneration of cardiomyocytes with functional decompensation. (Circ Res.

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Section: Discussionmentioning

confidence: 85%

Section: Cardiac Calpainopathy With Calpastatin Overexpressionmentioning

confidence: 99%

Cardiomyocyte Degeneration With Calpain Deficiency Reveals a Critical Role in Protein Homeostasis

Gálvez

Diwan

Odley

et al. 2007

Circulation Research

125

110

View full text Add to dashboard Cite

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“…Our data support the hypothesis that, in any population in the world, LGMD occurs most frequently in the sporadic form. [24][25][26][27][28][29][30][31][32] The possible reason for the high frequency of calpainopathy could be the allelic frequency differences between groups in India, a country that is larger than Europe, reflecting strong founder effects whose signatures have been maintained for thousands of years owing to endogamy. Thus, it is predicted that there will be an excess of recessive diseases in India.…”

Section: Discussionmentioning

confidence: 99%

Limb girdle muscular dystrophy type 2A in India: A study based on semi-quantitative protein analysis, with clinical and histopathological correlation

et al. 2010

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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: 97%

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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Clinical, pathological, and genetic features of limb-girdle muscular dystrophy type 2A with new calpain 3 gene mutations in seven patients from three Japanese families

Cited by 42 publications

References 34 publications

Cardiomyocyte Degeneration With Calpain Deficiency Reveals a Critical Role in Protein Homeostasis

Cardiomyocyte Degeneration With Calpain Deficiency Reveals a Critical Role in Protein Homeostasis

Limb girdle muscular dystrophy type 2A in India: A study based on semi-quantitative protein analysis, with clinical and histopathological correlation

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

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