title: Transgenic rabbits expressing mutant essential light chain do not develop hypertrophic cardiomyopathy.
abstract: Mutations in multiple sarcomeric proteins can cause familial hypertrophic cardiomyopathy. Although a M149V mutation in the myosin light chain is associated with the human disease, the data from transgenic (TG) mouse models are conflicting. When a human genomic fragment containing the M149V essential myosin light chain was used to generate TG mice, the phenotype was recapitulated. However, when the mouse cDNA containing the mutation was used to generate TG animals, no phenotype could be discerned. TG rabbits can be a valuable complement and extension to mouse-based TG models and we wished to determine whether expression of this mutation in the rabbit heart would result in the disease. The rabbit essential light chain cDNA was isolated, sequenced, the M149V mutation made and the cDNA placed into the beta-myosin heavy chain promoter, which efficiently drives cardiac expression in the rabbit ventricles. Multiple TG rabbit lines showing different levels of protein replacement were obtained. No discernible pattern of disease was apparent at the structural or functional levels at either the neonatal, juvenile or adult stages. We conclude that the M149V mutation is not causative for FHC when expressed in the rabbit within the context of the endogenous protein.
authors.affiliation: Children's Hospital Research Foundation, Cincinnati, Ohio, 45229-3039, USA.
authors.forename: Jeanne
authors.initials: J
authors.lastname: James
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kathy
authors.initials: K
authors.lastname: Wright
authors.forename: Sra
authors.initials: S
authors.lastname: Witt
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Glascock
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.forename: Raisa
authors.initials: R
authors.lastname: Klevitsky
authors.forename: Lisa
authors.initials: L
authors.lastname: Martin
authors.forename: Karen
authors.initials: K
authors.lastname: Yager
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbe
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism; D002932:Cineangiography; D018076:DNA, Complementary; D008969:Molecular Sequence Data; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D018994:Myosin Light Chains / Q000235:genetics* / Q000378:metabolism; D011817:Rabbits / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D018076:DNA, Complementary; D018994:Myosin Light Chains