| The deafness (dn) mouse is a recessive mouse model for two forms of human deafness, DFNB7 and DFNB11. The dn mouse shows deterioration of the stria vascularis and the Organ of Corti starting ten days after birth. Over the years many genes have been mapped to the dn region on mouse chromosome 19 between markers D19Mit14 and D19Mit111. Several of these genes, TMEM2, ZNF216, and Lpc1 have been rejected as the dn gene due to lack of mutations in both the mouse model and in humans. Linkage and FISH studies were consistent with the dn gene being within an inversion near marker D19Mit14. The presence of this inversion defined the dn interval and may contribute to the hearing loss. We have evaluated and characterized another candidate gene Transmembrane Cochlear expressed gene 1 (Tmc1). In addition, we have refined the order of markers in the dn region by genetic and physical mapping.; Tmc1 is a novel gene that contains mutations in the DFNB7/DFNB11/DFNA36 families and the Beethoven mouse model. In the dn mouse, Tmc1 has a large deletion which removes 1.6 kb of genomic sequence, including the coding sequence of exon 14. The coding sequence of Tmc1 was analyzed using numerous bioinformatic programs to determine its function or what type of protein family it belongs in. Because Tmc1 lacks any known protein motifs or domains, we used a bacteria two-hybrid system to find proteins that interact with Tmc1 in the cell. The full-length cDNA, two cytoplasmic loops and the C terminus were used as baits to screen a mouse testis cDNA library. The interaction detected by the bacteria two-hybrid screen between Tmc1 and protein kinase receptor A anchor protein (AKAP) was not confirmed using the Ga14 yeast two-hybrid system. The role of Tmc1 within the cell and how its mutations in both mice and man lead to hearing loss still need to be elucidated. |
