Mutations in a novel gene with transmembrane domains underlie Usher syndrome type 3

Usher syndrome type 3 (USH3) is an autosomal recessive disorder characteriz ed by progressive hearing loss, severe retinal degeneration, and variably p resent vestibular dysfunction, assigned to 3q21-q25. Here, we report on the positional cloning of the USH3 gene. By haplotype and linkage-disequilibri um analyses in Finnish carriers of a putative founder mutation, the critica l region was narrowed to 250 kb, of which we sequenced, assembled, and anno tated 207 kb. Two novel genes-NOPAR and UCRP-and one previously identified gene-H963-were excluded as USH3, on the basis of mutational analysis. USH3, the candidate gene that we identified, encodes a 120-amino-acid protein. F ifty-two Finnish patients were homozygous for a termination mutation, Y100X ; patients in two Finnish families were compound heterozygous for Y100X and for a missense mutation, M44K, whereas patients in an Italian family were homozygous for a 3-bp deletion leading to an amino acid deletion and substi tution. USH3 has two predicted transmembrane domains, and it shows no homol ogy to known genes. As revealed by northern blotting and reverse-transcript ase PCR, it is expressed in many tissues, including the retina.