title: Functional defects of a muscle-specific calpain, p94, caused by mutations associated with limb-girdle muscular dystrophy type 2A.
abstract: p94 (calpain3), a muscle-specific member of the calpain family, has been shown to be responsible for limb-girdle muscular dystrophy type 2A (LGMD2A), a form of autosomal recessive and progressive neuromuscular disorder. To elucidate the molecular mechanism of LGMD2A, we constructed nine p94 missense point mutants found in LGMD2A and analyzed their p94 unique properties. All mutants completely or almost completely lose the proteolytic activity against a potential substrate, fodrin. However, some of the mutants still possess autolytic activity and/or connectin/titin binding ability, indicating these properties are not necessary for the LGMD2A phenotypes. These results provide strong evidence that LGMD2A results from the loss of proteolysis of substrates by p94, suggesting a novel molecular mechanism leading to muscular dystrophies.
authors.affiliation: Laboratory of Molecular Structure and Functions, Department of Molecular Biology, Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ono
authors.forename: H
authors.initials: H
authors.lastname: Shimada
authors.forename: H
authors.initials: H
authors.lastname: Sorimachi
authors.forename: I
authors.initials: I
authors.lastname: Richard
authors.forename: T C
authors.initials: TC
authors.lastname: Saido
authors.forename: J S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: S
authors.initials: S
authors.lastname: Ishiura
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D019556:COS Cells; D002154:Calpain / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D064211:Connectin; D006801:Humans; D006868:Hydrolysis; D008840:Microfilament Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009136:Muscular Dystrophies / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011494:Protein Kinases / Q000378:metabolism; D013049:Spectrin
chemical_list: D002154:Calpain; D002352:Carrier Proteins; D064211:Connectin; D008840:Microfilament Proteins; D009124:Muscle Proteins; D011494:Protein Kinases; D013049:Spectrin; C577285:TTN protein, human; C078134:calpain p94