The goal of this project is to clone the gene for inherited, nonsyndromic, progressive hearing loss (DFNA1, MIM 124900) in the Monge kindred from Costa Rica. All deaf members of the Monge kindred live near the same town in Costa Rica and trace their ancestry to a single, deaf founder in the 18th century. Deafness in this kindred is inherited as an autosomal dominant, fully penetrant condition, generally beginning about age ten with loss of hearing at low frequencies and inevitably progressing by age 30 to bilateral deafness involving all frequencies. Intelligence, fertility, and life expectancy are normal. The expression of DFNA1 in this kindred is limited to deafness; it is not a syndrome involving multiple abnormalities. Thus this gene is likely to directly influence hearing loss. The gene for deafness in this kindred has been mapped by linkage analysis involving 147 informative relatives to a region of about l cM on chromosome 5q31. Work is now underway to identify DFNA1 using the approach of positional cloning, with the aim of accomplishing this task in the next three years. To date, a high-density genetic map of the region has been made and YACs identified which cover the' entire genomic region linked to DFNA 1. Candidate genes will be identified by exon trapping and by screening three cDNA libraries (human fibroblast, human cochlea, and guinea pig organ of Corti). Progressive hearing loss consistent with autosomal dominant inheritance in other families will be mapped to determine whether their deafness may be due to other mutations in DFNA1. Identifying the gene for deafness in the Monge kindred could contribute to the general understanding of genetically influenced hearing loss.
