The Usher syndromes

Mutations in the gene (MYO7A) encoding myosin-Vlla, a member of the large s uperfamily of myosin motor proteins that move on cytoplasmic actin filament s, and in the USH2A gene, which encodes a novel protein resembling an extra cellular matrix protein or a cell adhesion molecule, both cause Usher syndr ome (USH), a clinically heterogeneous autosomal recessive disorder comprisi ng hearing and visual impairment. Patients with USH1 have severe to profoun d congenital hearing impairment, vestibular dysfunction, and retinal degene ration beginning in childhood, while those with USH2 have moderate to sever e hearing impairment normal vestibular function, and later onset of retinal degeneration. USH3 is characterized by progressive hearing loss and variab le age of onset of retinal degeneration. The phenotype resulting from MYO7A and USH2A mutations is variable. While most MYO7A mutations cause USH1, so me cause nonsyndromic hearing impairment, and one USH3 phenotype has been d escribed. USH2A mutations cause atypical USH as well as USH2. MYO7A is on c hromosome region 11q13 and USH2A is on 1q41. Seven other USH genes have bee n mapped but have nor yet been identified. USH1A, USH1C, USH1D, USH1E, and USH1F have been assigned to chromosome bands 14q32, 11p15.1, 10q, 21q21, an d 10, respectively, while USH2B is on 5q, and USH3 is at 3q21-q25. Myosin V lla mutations also result in the shaker-1 (sh1) mouse, providing a model fo r functional studies. One possibility is that myosin-Vlla is required for l inking stereocilia in the sensory hair bundle; another is that it may be ne eded for membrane trafficking. The ongoing studies of myosin-Vlla, the USH2 A protein, and the yet to be identified proteins encoded by the other USH g enes will advance understanding of the Usher syndromes and contribute to th e development of effective therapies. (C) 2000 Wiley-Liss, Inc.