Defective Myosin Genes in Mutant Mice and Human Diseases

Myosins are highly divergent actin‐based molecular motors. In five of eight classes expressed in mammals, defects in genes have been identified in mutant mice and/or human diseases. A mutated myosin II‐7 gene is one of the causes of human familial hypertrophic cardiomyopathy (FHC). The defective myosin Va gene is responsible for Griscelli disease, which is characterized by partial albinism and immunodeficiency, while in its mouse homologue coat color dilution is seen with or without neurological defects. There are three classes of myosins, VI, VII and XV, that are essential in the inner ear function. In humans, mutations in the VIIa gene are associated with three deafness‐related diseases, Usher 1B/DFNB2/DFNA11, providing the first example of exhibition of recessive‐ and dominant‐inherited disorders by different mutations in a single myosin gene. There are variations in phenotype between human diseases and their mouse models, which appear to be explicable on the basis of differences in tissue expression patterns of the given myosin between mouse and man. In FHC and Usher 1BDFNB2DFNA11, a wide spectrum of clinical symptoms are observed. Evidence has accumulated suggesting that the more functionally important the mutation site of the molecule, the more serious and severe the symptoms, although involvement of additional factors such as modifier genes and genetic background can not be ruled out. Molecular genetic analyses of a variety of dilute alleles in mice have greatly facilitated our understanding of genotype‐phenotype correlations, including information about structurally and functionally important domains of the myosin Va protein and cell‐type‐specific functions of different isoforms produced by alternative splicing.