The W4R-MLP missense mutation, present in up to 1% of Caucasians, caused age- and gene dosage-dependent hypertrophic cardiomyopathy and heart failure in knock-in animal models.
Does the W4R-MLP mutation cause cardiomyopathy and heart failure in an in vivo animal model?
The W4R-MLP mutation, present in up to 1% of Caucasians, causes hypertrophic cardiomyopathy and heart failure in an animal model, suggesting it may significantly contribute to human cardiovascular disease.
Rationale : We previously discovered the human 10T→C (Trp4Arg) missense mutation in exon 2 of the muscle LIM protein (MLP, CSRP3) gene. Objective : We sought to study the effects of this single-nucleotide polymorphism in the in vivo situation. Methods and Results : We now report the generation and detailed analysis of the corresponding Mlp W4R/+ and Mlp W4R/W4R knock-in animals, which develop an age- and gene dosage–dependent hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost complete loss of contractile reserve under catecholamine induced stress. In addition, evidence for skeletal muscle pathology, which might have implications for human mutation carriers, was observed. Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels in hearts of heterozygous and homozygous W4R-MLP knock-in animals. We also detected a weaker in vitro interaction of telethonin with W4R-MLP than with wild-type MLP. These alterations may contribute to an increased nuclear localization of W4R-MLP, which was observed by immunohistochemistry. Conclusions : Given the well-known high frequency of this mutation in Caucasians of up to 1%, our data suggest that W4R-MLP might contribute significantly to human cardiovascular disease.
Knöll et al. (Fri,) conducted a other in Cardiomyopathy. Mlp W4R/+ and Mlp W4R/W4R knock-in vs. Wild-type was evaluated on Hypertrophic cardiomyopathy and heart failure phenotype. The W4R-MLP missense mutation, present in up to 1% of Caucasians, caused age- and gene dosage-dependent hypertrophic cardiomyopathy and heart failure in knock-in animal models.