Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 arecaused by allelic mutations of the novel cadherin-like gene CDH23

Genes causing nonsyndromic autosomal recessive deafness (DFNB12) and deafne ss associated with retinitis pigmentosa and vestibular dysfunction (USH1D) were previously mapped to overlapping regions of chromosome 10q21-q22. Seve n highly consanguineous families segregating nonsyndromic autosomal recessi ve dearness were analyzed to refine the DFNB12 locus. In a single family, a critical region was defined between D10S1694 and D1OS173 7, similar to0.55 cM apart. Eighteen candidate genes in the region were sequenced. Mutations in a novel cadherin-like gene, CDH23, were found both in families with DFN B12 and in families with USH1D. Six missense mutations were found in five f amilies with DFNB12, and two nonsense and two frameshift mutations were fou nd in four families with USH1D. A northern blot analysis of CDH23 showed a 9.5-kb transcript expressed primarily in the retina. CDH23 is also expresse d in the cochlea, as is demonstrated by polymerase chain reaction amplifica tion from cochlear cDNA.