Mutations in a Novel Gene with Transmembrane Domains Underlie Usher Syndrome Type 3

• Published in: American journal of human genetics 2001-10, Vol.69 (4), p.673-684
• Main Authors: Joensuu, Tarja, Hämäläinen, Riikka, Yuan, Bo, Johnson, Cheryl, Tegelberg, Saara, Gasparini, Paolo, Zelante, Leopoldo, Pirvola, Ulla, Pakarinen, Leenamaija, Lehesjoki, Anna-Elina, de la Chapelle, Albert, Sankila, Eeva-Marja
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - genetics; Base Sequence; Biological and medical sciences; Chromosomes, Human, Pair 3 - genetics; Cloning, Molecular; Contig Mapping; Deafness - genetics; Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology; Expressed Sequence Tags; Female; Finland; Founder Effect; Gene Expression Profiling; Genetic Linkage - genetics; H963 gene; Haplotypes - genetics; Humans; Linkage Disequilibrium - genetics; Male; Medical sciences; Membrane Proteins - chemistry; Membrane Proteins - genetics; Molecular Sequence Data; Mutation - genetics; Non tumoral diseases; NOPAR gene; Otorhinolaryngology. Stomatology; Pedigree; Protein Structure, Secondary; Protein Structure, Tertiary; Retina - metabolism; Retinal Degeneration - genetics; RNA, Messenger - analysis; RNA, Messenger - genetics; Syndrome; UCRP gene; USH3 gene
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/323610

Usher syndrome type 3 (USH3) is an autosomal recessive disorder characterized by progressive hearing loss, severe retinal degeneration, and variably present vestibular dysfunction, assigned to 3q21-q25. Here, we report on the positional cloning of the USH3 gene. By haplotype and linkage-disequilibrium analyses in Finnish carriers of a putative founder mutation, the critical region was narrowed to 250 kb, of which we sequenced, assembled, and annotated 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. Fifty-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 substitution. USH3 has two predicted transmembrane domains, and it shows no homology to known genes. As revealed by northern blotting and reverse-transcriptase PCR, it is expressed in many tissues, including the retina.