GENETIC-MAPPING REFINES DFNB3 TO 17P11.2, SUGGESTS MULTIPLE ALLELES OF DFNB3, AND SUPPORTS HOMOLOGY TO THE MOUSE MODEL SHAKER-2

The nonsyndromic congenital recessive deafness gene, DFNB3, first iden tified in Bengkala, Bali, was mapped to a similar to 12-cM interval on chromosome 17. New short tandem repeats (STRs) and additional DNA sam ples were used to identify recombinants that constrain the DFNB3 inter val to less than or similar to 6 cM on 17p11.2. Affected individuals f rom Bengkala and affected members of a family with hereditary deafness who were from Bila, a village neighboring Bengkala, were homozygous f or the same alleles for six adjacent STRs in the DFNB3 region and were heterozygous for other distal markers, thus limiting DFNB3 to an simi lar to 3-cM interval. Nonsyndromic deafness segregating in two unrelat ed consanguineous Indian families, M21 and I-1924, were also linked to the DFNB3 region. Haplotype analysis indicates that the DFNB3 mutatio ns in the three pedigrees most likely arose independently and suggests that DFNB3 makes a significant contribution to hereditary deafness wo rldwide. On the basis of conserved synteny, mouse deafness mutations s haker-2 (sh2) and sh2(J) are proposed as models of DFNB3. Genetic mapp ing has refined sh2 to a 0.6-cM interval of chromosome 11. Three homol ogous genes map within the sh2 and DFNB3 intervals, suggesting that sh 2 is the homologue of DFNB3.