Abstract: Protein complexes consisting of a cyclin dependent kinase CDK4 and cyclin D control passage through the G1 checkpoint of the cell cycle by phosphorylating the retinoblastoma protein. The ability of these complexes to phosphorylate RB is inhibited by a family of low molecular weight proteins, including p16, p15 and p18. Germline mutations in the p16 gene have been identified in approximately half of families with hereditary A mutation is described in CDK4 in two unrelated melanoma families that do not carry germline p16 mutations. This CDK4-R24C mutation was detected in 11/11 melanoma patients, 2/17 unaffecteds and 0/5 spouses. This mutation has a specific effect of the p16 binding domain of CDK4, but has no effect on its ability to bind cyclin D and form a functional kinase. Therefore, the germline R24C mutation in CDK4 generates a dominant oncogene that is resistant to normal physiological inhibition by p16.

Abstract: The gene responsible for an autosomal dominant con-rod retinal dystrophy is identified, TULP2. The genes are used to produce the encoded protein; in screening for compositions that modulate the expression or function of TULP2 protein; and in studying associated physiological pathways.