Usher syndrome type I causes profound congenital deafness, retinitis pigmentosa, and vestibular areflexia. At least three genes are responsible; these have been localized to chromosomes 14q, 11q, and 11p and are called USH1a, USH1b, and USH1c, respectively. Our work has concentrated primarily on the USH1b gene on 11q. We have found that mutations at USH1b are responsible for about 85% of all cases of the more severe type I Usher syndrome and that this gene lies within a 0.5 cMo segment between the markers OMP1 and D11S911/S906. Furthermore, we have now constructed a preliminary YAC contig for that region. We propose to complete the YAC contig for the region D11S787-OMP1-USH1b- D11S911-D11S937 and to construct an STS and rare cutter restriction enzyme map. The relevant YAC clones will be used to construct cosmid libraries from which a cosmid contig for OMP1-USH1b-D11S911 will be assembled. Clones from the critical region will be used to a) screen for polymorphism which could reduce the critical region containing the USH1b gene and to look for linkage disequilibrium and b) to screen for microdeletions that might point directly to the USH1b gene. Expressed sequences from the region will be detected by: exon trapping, screening cDNA libraries, searching for hypomethylated CpG islands, screening for evolutionarily conserved sequences, and computer analysis of DNA sequences. These expressed sequences are candidates for the USH1b gene and will be studied in detail; the USH1b gene will be identified on the basis of finding mutations in affected individuals not present in unaffected persons and which would result in drastically altered (or null) expression of the putative mutant USH1b gene. Once the USH1b gene is identified we intend to determine its structure and function, to examine the tissue distribution of expression, and determine if isoforms or variants exist. Our large series of Usher I patients will be studied to determine the nature and frequency of different USH1b mutations. Last, since Usher syndrome is rare in African-Americans, we will determine if Usher syndrome occurs in the original African population. About l of 20,000 individuals is affected with Usher syndrome. It has been estimated that 5% of all children in schools for the deaf have Usher syndrome, thus it is one of the most frequent causes of congenital deafness. the most common subtype of which is caused by mutations at the USH1b locus. The burden caused by the loss of the two most vital senses is tremendous. It isolates patients from the mainstream of society resulting in severe psychological stress and reduces their ability to act independently. The answers to many intriguing questions regarding Usher syndrome will not be available until the genes are cloned. Better understanding of the etiology of Usher syndrome will provide critical information about the function and expression of the USH genes. Such knowledge has important implications for genetic counseling and effective treatment.
| Sadeghi, Mehdi; Cohn, Edward S; Kimberling, William J et al. (2005) Audiological and vestibular features in affected subjects with USH3: a genotype/phenotype correlation. Int J Audiol 44:307-16 |
| Pennings, Ronald J E; Huygen, Patrick L M; Orten, Dana J et al. (2004) Evaluation of visual impairment in Usher syndrome 1b and Usher syndrome 2a. Acta Ophthalmol Scand 82:131-9 |
| Pennings, Ronald J E; Te Brinke, Heleen; Weston, Michael D et al. (2004) USH2A mutation analysis in 70 Dutch families with Usher syndrome type II. Hum Mutat 24:185 |
| Pennings, Ronald J E; Topsakal, Vedat; Astuto, Lisa et al. (2004) Variable clinical features in patients with CDH23 mutations (USH1D-DFNB12). Otol Neurotol 25:699-706 |
| Astuto, Lisa M; Kelley, Philip M; Askew, James W et al. (2002) Searching for evidence of DFNB2. Am J Med Genet 109:291-7 |
| Astuto, L M; Bork, J M; Weston, M D et al. (2002) CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness. Am J Hum Genet 71:262-75 |
| Astuto, L M; Weston, M D; Carney, C A et al. (2000) Genetic heterogeneity of Usher syndrome: analysis of 151 families with Usher type I. Am J Hum Genet 67:1569-74 |
| Orten, D J; Weston, M D; Kelley, P M et al. (2000) Erratum: analysis of DNA elements that modulate myosin VIIa expression in humans. Hum Mutat 15:114-5 |
| Pieke-Dahl, S; Moller, C G; Kelley, P M et al. (2000) Genetic heterogeneity of Usher syndrome type II: localisation to chromosome 5q. J Med Genet 37:256-62 |
| Orten, D J; Weston, M D; Kelley, P M et al. (1999) Analysis of DNA elements that modulate myosin VIIA expression in humans. Hum Mutat 14:354 |
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