The goal of this project is to map a gene for human deafness in a large kindred in which hereditary low frequency hearing loss (LFHL I, MIM 12490) is autosomal dominant and fully penetrant. Low tone deafness in this kindred generally begins by age ten and inevitably progresses by age 30 to bilateral deafness involving all frequencies. Intelligence, fertility, and life expectancy are normal. All affected relatives live near the same town in Costa Rica and trace their ancestry to a single, affected founder in the 18th century. At present, 105 living members of the kindred are informative for genetic linkage studies, yielding 88 meioses informative for deafness, a lod score > 3 for an informative marker within 40% recombination of LFHL I, and enough information to map markers to approximately 1cM from LFHL I. We have established EBV-transformed cell lines for two sibships and plan to sample and transform the other informative individuals. LFHL I will be mapped to chromosomal region by linkage analysis using polymorphic probes from all chromosome arms. The kindred will be screened for all existing markers in the region and LFHL I located on a multipoint map. New polymorphisms very closely linked to LFHL I will be obtained by screening a chromosome-specific library and/or radiation hybrids containing the critical chromosomal region with short sequences that frequently yield repeat polymorphisms. These will be localized using hybrid cell lines, as necessary, and mapped genetically in the CEPH families and the LFHL I kindred. Any candidate gene for deafness in this region will be screened for polymorphism and tested for linkage to deafness in the kindred. Any candidate gene segregating with deafness in the kindred will be sequenced in affected and unaffected relatives. Ideally, this project will identify a gene for human deafness and the lesion associated with the disease. Minimally this project will map LFHL I to within approximately 1 cM, enabling future cloning of the responsible gene. Identifying the gene for deafness in this kindred could contribute to the general understanding of genetically influenced human deafness, particularly because the expression of LFHL I in this kindred is limited to deafness; it is not a syndrome involving multiple abnormalities. Thus, this gene must directly influence hearing loss.
