title: The muscular dystrophy with myositis (mdm) mouse mutation disrupts a skeletal muscle-specific domain of titin.
abstract: Muscular dystrophy with myositis (mdm) is a recessive mouse mutation that causes severe and progressive muscular degeneration. Here we report the identification of the mdm mutation as a complex rearrangement that includes a deletion and a LINE insertion in the titin (Ttn) gene. Mutant allele-specific splicing results in the deletion of 83 amino acids from the N2A region of TTN, a domain thought to bind calpain-3 (CAPN3) the product of the human limb-girdle muscular dystrophy type 2A (LGMD2A) gene. The Ttn(mdm) mutant mouse may serve as a model for human tibial muscular dystrophy, which maps to the TTN locus at 2q31 and shows a secondary reduction of CAPN3 similar to that observed in mdm skeletal muscle. This is the first demonstration that a mutation in Ttn is associated with muscular dystrophy and provides a novel animal model to test for functional interactions between TTN and CAPN3.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Garvey
authors.forename: Chandrika
authors.initials: C
authors.lastname: Rajan
authors.forename: Allen P
authors.initials: AP
authors.lastname: Lerner
authors.forename: Wayne N
authors.initials: WN
authors.lastname: Frankel
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
mesh_terms: D000818:Animals; D002154:Calpain / Q000378:metabolism; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D064211:Connectin; D017353:Gene Deletion; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics*; D018482:Muscle, Skeletal / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics*; D016254:Mutagenesis, Insertional; D009220:Myositis / Q000235:genetics*; D010446:Peptide Fragments; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics*; D017434:Protein Structure, Tertiary
chemical_list: D064211:Connectin; D008024:Ligands; D009124:Muscle Proteins; D010446:Peptide Fragments; C577285:TTN protein, human; D011494:Protein Kinases; D002154:Calpain; C491373:Capn3 protein, mouse; C078134:calpain p94