1. We previously identified and reported a gene underlying hereditary, nonsyndromic recessive deafness at the DFNB7/B11 locus and nonsyndromic dominant progressive hearing loss at the DFNA36 locus on chromosome 9q31. The gene, TMC1, is predicted to encode a protein with at least 6 transmembrane domains, but otherwise has no sequence similarity to any known genes. We have now identified 6 other TMC genes, TMC2-7, and a pseudogene with sequence similarity to TMC1. Tmc1 is expressed in the inner and outer hair cells of the mouse cochlea, where it may act as an ion channel or transporter. We have established several heterologous expression systems for studying potential functional activities and interactions of TMC1, TMC2, and TMC3. 2. We have identified Tmc1 mutations in a mouse model for DFNB7/B11, the deafness mouse, and in a mouse model for DFNA36, the Beethoven mouse. These mouse models are characterized by rapid neurosensory hair cell degeneration in the inner ear. 3. We have completed a molecular genetic survey of Pendred syndrome gene (PDS) mutations in deaf individuals from south and east Asia, which contains nearly one half of the global population. Our results indicate that PDS mutations are a leading cause of deafness in these populations, comparable to that observed in western/European populations. PDS mutational events are common and account for a novel, diverse allele series that is unique to each large ethnic group. Our study demonstrates that genetic testing for PDS mutations in deaf individuals should be guided by the patient's ethnicity and the distribution and frequencies of mutant PDS alleles in the reference population. 4. We have made progress in our effort to positionally clone the gene mutated in the mouse Twirler strain. Heterozygous Twirler mice have inner ear malformations and obesity, whereas homozygous mice are born with cleft palate and die at birth. We have analyzed nearly 2500 meiotic chromosomes from a mapping backcross and refined the critical interval containing the Twirler gene to approximately 1 Mb. The physical map and nucleotide sequence of this interval is known and contains 10 candidate genes which we are currently sequencing to identify the Twirler mutation. 4. We have identified the genetic basis for a distinctive form of hereditary nonsyndromic hearing impairment in which there is prelingual profound deafness at high frequencies, with variably penetrant postlingual progressive loss of hearing at lower frequencies. The affected individuals are homozygous for a missense mutation, F1888S, of CDH23 (encoding cadherin 23). CDH23 mutations can also cause type 1D Usher syndrome, a recessive disorder comprising profound congenital deafness and retinitis pigmentosa, which causes progressive blindness. Frameshift, splice site, nonsense mutations, and some missense mutations of CDH23 are associated with Usher syndrome, whereas other missense mutations cause moderate-to-severe, nonsyndromic deafness DFNB12. We identified an individual that was compound heterozygous for F1888S (a DFNB12 allele) and a frameshift (Usher) allele of CDH23. Her phenotype was profound congenital deafness, normal retinal function, and normal vestibular function. This suggests a model in which DFNB12 alleles are dominant over USH1D alleles in the visual and vestibular systems, whereas USH1D alleles appear to be dominant over DFNB12 alleles in the auditory system.
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