Genes causing nonsyndromic autosomal recessive deafness (DFNB12) and deafness associated with retinitis pigmentosa and vestibular dysfunction (USH1D) were previously mapped to overlapping regions of chromosome 10q21-q22. Seven highly consanguineous families segregating nonsyndromic autosomal recessive deafness were analyzed to refine the DFNB12 locus. In a single family, a critical region was defined between D10S1694 and D10S1737, approximately 0.55 cM apart. Eighteen candidate genes in the region were sequenced. Mutations in a novel cadherin-like gene, CDH23, were found both in families with DFNB12 and in families with USH1D. Six missense mutations were found in five families with DFNB12, and two nonsense and two frameshift mutations were found 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 expressed in the cochlea, as is demonstrated by polymerase chain reaction amplification from cochlear cDNA.

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The three-dimensional structure of the eye lens protein, bovine gamma-crystallin II, has been determined at 2.6 A resolution. The protein has a tow domain beta-structure, folded into four remarkably similar 'Greed key' motifs, and shows the highest internal symmetry of any protein studied by X-ray analysis. Although the symmetrical structure seems very stable, the arrangement of the sulphydryl groups would allow intramolecular cross-linking leading to possible destabilization, and intermolecular cross-linking leading to aggregation, both of which may be important to cataract formation.

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The lens structural protein -crystallin and the metabolic enzyme argininosuccinate lyase (ASL; Largininosuccinate argine-lyase, EC 4.3.2.1) have striking sequence similarity. We have demonstrated that duck & crystallin has enormously high ASL activity, while chicken 6crystallin has lower but significant activity. The lenses of these birds had much greater ASL activity than other tissues, suggesting that ASL is being expressed at unusually high levels as a structural component. In Southern blots ofhuman genomic DNA, chicken 61-crystallin cDNA hybridized only to the human ASL gene; moreover, the two chicken 8-crystallin genes accounted for all the sequences in the chicken genome able to cross-hybridize with a human ASL cDNA, with preferential hybridization to the 62 gene. Correlations of enzymatic activity and recent data on mRNA levels in the chicken lens suggest that ASL activity depends on expression of the 82-crystallin gene.The data indicate that the same gene, at least in ducks, encodes two different functions, an enzyme (ASL) and a structural protein (&crystallin), although in chickens specialization and separation of functions may have occurred.

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