title: Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A.
abstract: Limb-girdle muscular dystrophies (LGMDs) are a group of inherited diseases whose genetic etiology has yet to be elucidated. The autosomal recessive forms (LGMD2) constitute a genetically heterogeneous group with LGMD2A mapping to chromosome 15q15.1-q21.1. The gene encoding the muscle-specific calcium-activated neutral protease 3 (CANP3) large subunit is located in this region. This cysteine protease belongs to the family of intracellular calpains. Fifteen nonsense, splice site, frameshift, or missense calpain mutations cosegregate with the disease in LGMD2A families, six of which were found within La Réunion island patients. A digenic inheritance model is proposed to account for the unexpected presence of multiple independent mutations in this small inbred population. Finally, these results demonstrate an enzymatic rather than a structural protein defect causing a muscular dystrophy, a defect that may have regulatory consequences, perhaps in signal transduction.
authors.affiliation: Généthon, Evry, France.
authors.forename: I
authors.initials: I
authors.lastname: Richard
authors.forename: O
authors.initials: O
authors.lastname: Broux
authors.forename: V
authors.initials: V
authors.lastname: Allamand
authors.forename: F
authors.initials: F
authors.lastname: Fougerousse
authors.forename: N
authors.initials: N
authors.lastname: Chiannilkulchai
authors.forename: N
authors.initials: N
authors.lastname: Bourg
authors.forename: L
authors.initials: L
authors.lastname: Brenguier
authors.forename: C
authors.initials: C
authors.lastname: Devaud
authors.forename: P
authors.initials: P
authors.lastname: Pasturaud
authors.forename: C
authors.initials: C
authors.lastname: Roudaut
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002154:Calpain / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15; D004247:DNA / Q000097:blood; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D015870:Gene Expression; D005820:Genetic Testing; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009692:Nucleic Acid Heteroduplexes; D016133:Polymerase Chain Reaction / Q000379:methods; D015183:Restriction Mapping; D016415:Sequence Alignment
chemical_list: D009692:Nucleic Acid Heteroduplexes; D004247:DNA; D002154:Calpain