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

T. Joensuu, R. Hämäläinen, B. Yuan, C. Johnson, S. Tegelberg, P. Gasparini, L. Zelante, U. Pirvola, L. Pakarinen, A. E. Lehesjoki, A. De la Chapelle, E. M. Sankila

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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.

Original languageEnglish
Pages (from-to)673-684
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 2001

ASJC Scopus subject areas

  • Genetics


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