FURTHER REFINEMENT OF THE USHER 2A LOCUS AT 1Q41

Usher syndrome (USH) is characterised by congenital sensorineural hear ing loss and progressive pigmentary retinopathy. All three subtypes (U SH1, USH2, and USH3) are inherited as recessive traits. People with Us her type 2 (USH2) have normal vestibular responses and moderate to sev ere hearing loss. These syndromes have been found to be genetically he terogeneous, with a single locus for USH2 at 1q41 (USH2A), six loci fo r USH1, and one for USH3. Some USH2 families have been excluded fi om the 1q41 locus suggesting that a second, as yet unidentified, locus (U SH2B) must exist. Linkage studies suggest that around 90% of USH2 fami lies are USH2A. Four USH2 families were analysed for linkage to marker s flanking the USH2A locus. In one of these families a recombination e vent was observed in an affected subject which excludes the USH2A gene from proximal to the marker AFM143XF10 and defines this as the new ce ntromeric flanking marker for the USH2A locus. A further recombination event in another patient from this family confirmed AFM144XF2 as the telomeric flanking marker. The interval between these polymorphic mark ers is estimated to be 400 kb. This region is completely contained in each of three YACs from the CEPH library: 867g9, 919h3, and 848b9. Thi s refinement more than halves the critical genetic interval and will g reatly facilitate positional cloning of the USH2A gene.