HEARING-LOSS IN THE RBF DNJ MOUSE, A PROPOSED ANIMAL-MODEL OF USHER-SYNDROME TYPE IIA/

The Usher syndromes (US) are a group of inherited disorders that featu re autosomal recessive neurosensory hearing loss or deafness with reti nitis pigmentosa (RP). Moderate to severe non-progressive high frequen cy hearing loss with RP and normal vestibular function describes Usher syndrome type IIa, which has been localized to 1q41. Severe retinal d egeneration in the inbred mouse strain RBF/DnJ is caused by rd3, a rec essive gene located on mouse chromosome 1 distal to akp1 in a region w hich is orthologous to human 1q32-q42. We evaluated rd3 as a candidate for orthology with USH2A by first reducing and refining the relativel y broad region in which rd3 is thought to reside. DNA of offspring fro m an RBF/DnJ x MOLF/Ei backcross was genotyped with PCR markers closel y flanking the predicted location of rd3. Our haplotype analysis re-po sitioned rd3 to a 3.6 cM region between markers D1Mit273 (cen) and D1M it209 (tel), consistent with the expected position of an USH2A murine orthologue. Consequently, rd3 is a positional candidate for Usher type IIa. Next we assessed the rd3/rd3 audiological phenotype to see how c losely it paralleled that of Usher IIa. Audiological evaluation of mic e at various ages revealed evidence of high frequency progressive hear ing loss, previously unreported in the RBF/DnJ strain. However, this n ewly discovered hearing deficit was observed to be inherited independe ntly of rd3, establishing that a completely different gene is responsi ble.