DEFECTIVE MYOSIN VIIA GENE RESPONSIBLE FOR USHER SYNDROME TYPE 1B

USHER syndrome represents the association of a hearing impairment with retinitis pigmentosa(1) and is the most frequent cause of deaf-blindn ess in humans. it is inherited as an autosomal recessive trait which i s clinically and genetically heterogeneous(2,3). Some patients show ab normal organization of microtubules in the axoneme of their photorecep tors cells (connecting cilium)(4-6), nasal ciliar cells(7) and sperm c ells(5), as well as widespread degeneration of the organ of Corti(8). Usher syndrome type 1 (USH1) is characterized by a profound congenital sensorineural hearing loss, constant vestibular dysfunction and prepu bertal onset of retinitis pigmentosa. Of three different genes respons ible for USH1(9-11) USH1B maps to 11q13.5 (ref. 10) and accounts for a bout 75% of USH1 patients(2,3). The mouse deafness shaker-1 (sh1) muta tion has been localized to the homologous murine region(12,13). Taking into account the cytoskeletal abnormalities in USH patients, the iden tification of a gene encoding an unconventional myosin as a candidate for shaker-1 (ref. 14) led us to consider the human homologue as a goo d candidate for the gene that is defective in USH1B. Here we present e vidence that a gene encoding myosin VIIA is responsible for USH1B. Two different premature stop codons, a six-base-pair deletion and two dif ferent missense mutations were detected in five unrelated families. In one of these families, the mutations were identified in both alleles. These mutations, which are located at the amino-terminal end of the m otor domain of the protein, are likely to result in the absence of a f unctional protein. Thus USH1B appears as a primary cytoskeletal protei n defect. These results implicate the genes encoding other unconventio nal myosins and their interacting proteins as candidates for other gen etic forms of Usher syndrome.