Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A

Richard, Isabelle; Broux, Odile; Allamand, V.; Fougerousse, Françoise; Chiannilkulchai, Nuchanard; Bourg, Nathalie; Brenguier, L.; Devaud, Catherine; Pasturaud, Patricia; Roudaut, Carinne; Hillaire, Dominique; Passos-Bueno, Maria-Rita; Zatz, Mayana; Tischfield, Jay A.; Fardeau, Michel; Jackson, Charles E.; Cohen, Daniel; Beckmann, Jacques S.

doi:10.1016/0092-8674(95)90368-2

Cited by 894 publications

(555 citation statements)

References 39 publications

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“…Finally, the recent report (Busquets et al, 2000) that the expression of the muscle-specific calpain p94 is significantly reduced may also be relevant to the present findings. The loss of function of this particular calpain is responsible for limb girdle muscular dystrophy type 2A (Richard et al, 1995) and a suggested function of this enzyme is to protect some muscle proteins from degradation by ubiquitous m-and µ-calpains (Kinbara et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Activation of Ca2+-dependent proteolysis in skeletal muscle and heart in cancer cachexia

et al. 2001

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Cachexia is a syndrome characterized by profound tissue wasting that frequently complicates malignancies. In a cancer cachexia model we have shown that protein depletion in the skeletal muscle, which is a prominent feature of the syndrome, is mostly due to enhanced proteolysis. There is consensus on the views that the ubiquitin/proteasome pathway plays an important role in such metabolic response and that cytotoxic cytokines such as TNFα are involved in its triggering (Costelli and Baccino, 2000), yet the mechanisms by which the relevant extracellular signals are transduced into protein hypercatabolism are largely unknown. Moreover, little information is presently available as to the possible involvement in muscle protein waste of the Ca 2+ -dependent proteolysis, which may provide a rapidly activated system in response to the extracellular signals. In the present work we have evaluated the status of the Ca 2+ -dependent proteolytic system in the gastrocnemius muscle of AH-130 tumour-bearing rats by assaying the activity of calpain as well as the levels of calpastatin, the natural calpain inhibitor, and of the 130 kDa Ca 2+ -ATPase, both of which are known calpain substrates. After tumour transplantation, total calpastatin activity progressively declined, while total calpain activity remained unchanged, resulting in a progressively increasing unbalance in the calpain/calpastatin ratio. A decrease was also observed for the 130 kDa plasma membrane form of Ca 2+ -ATPase, while there was no change in the level of the 90 kDa sarcoplasmic Ca 2+ -ATPase, which is resistant to the action of calpain. Decreased levels of both calpastatin and 130 kDa Ca 2+ -ATPase have been also detected in the heart of the tumour-bearers. These observations strongly suggest that Ca 2+ -dependent proteolysis was activated in the skeletal muscle and heart of tumour-bearing animals and raise the possibility that such activation may play a role in sparking off the muscle protein hypercatabolic response that characterizes cancer cachexia. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Section: Discussionmentioning

confidence: 99%

Activation of Ca2+-dependent proteolysis in skeletal muscle and heart in cancer cachexia

et al. 2001

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“…This condition is due to inactivating mutations occurring in the CAPN3 gene which encodes a skeletal muscle enzyme named calpain 3 4, 5. This enzyme is a skeletal muscle‐specific form of calpains, a family of intracellular calcium‐dependent cysteine proteases mediating their activity through limited proteolysis of various target substrates 6.…”

Section: Introductionmentioning

confidence: 99%

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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“…The calpain family is divided into two groups, typical and atypical. The first group (calpains 1,2,3,8,9,11,12,14), are known as typical calpains because they are comprised of four domains including the Ca 2+ binding domain (domain IV). The second group (calpains 5,6,7,10,13,15) are known as atypical calpains because they lack the Ca 2+ binding domain (domain IV) [1].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial calpain 10 activity and expression in the kidney of multiple species

Giguere¹,

Covington²,

Schnellmann³

2008

Biochemical and Biophysical Research Communications

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Calpains, Ca 2+ -activated cysteine proteases, have been implicated in the progression of multiple disease states. We recently identified calpain 10 as a mitochondrial calpain that is involved in Ca 2+ -induced mitochondrial dysfunction. The goals of this study were to characterize the expression and activity of renal mitochondrial calpain 10 in rabbit, mouse, and rat. Using shRNA technology and immunoblot analysis three previously postulated splice variants of calpain 10 were identified (50, 56, and 75 kDa). SLLVY-AMC zymography and immunoblot analysis was used to directly link calpeptin-sensitive calpain activity to calpain 10 splice variants. Rabbit, mouse, and rat kidney mitochondria contained 75 kDa (calpain 10a), 56 kDa (calpain 10c or 10d), and 50 kDa (calpain 10e). Interestingly, zymography yielded distinct bands of calpain activity containing multiple calpain 10 splice variants in all species. These results provide evidence that several previously postulated splice variants of calpain 10 are localized to the mitochondria in kidneys of rabbits, rats and mice.

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Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A

Cited by 894 publications

References 39 publications

Activation of Ca2+-dependent proteolysis in skeletal muscle and heart in cancer cachexia

Activation of Ca2+-dependent proteolysis in skeletal muscle and heart in cancer cachexia

Natural history of LGMD2A for delineating outcome measures in clinical trials

Mitochondrial calpain 10 activity and expression in the kidney of multiple species

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