Grant: Operating Grant

Calcium homeostasis in cells is of critical importance for the proper functioning of cells in all tissues in our body. Our laboratory has a long standing interest in the SLC24 gene family of NCKX proteins that are important for proper calcium homeostasis in retinal rod and cone photoreceptors, in many neurons in the brain and in pigment producing cells in the skin and in the eye. We conduct structure-function studies of NCKX proteins to elucidate how NCKX proteins work. One part of our research concerns the role of NCKX5 in pigment synthesis in the skin and in the eye. The human population displays a striking variation in skin, hair and eye pigmentation and the underlying molecular mechanism remains one of the outstanding problems in human biology. Work during the past several years has yielded great progress in the identification of sequence variants in the few genes within the human genome that are associated with variations in human skin pigmentation. One of the more striking examples is the recent identification of a sequence variant in the SLC24a5 gene (encoding the fifth member of the family of NCKX proteins) that, when present on both chromosomes, is responsible for light skin in people from European descent. It is possible that the same sequence variant constitutes a risk factor for people from European descent for developing age-related macular degeneration, the most prevalent blinding disease in the elderly. Other members of the NCKX family are involved in calcium transport, although NCKX5 function in pigment producing cells remains elusive. NCKX5 is also found in the eye where it plays a major role in melanin pigment synthesis in the retinal pigment epithelium. In this application we propose experiments to elucidate the role of the NCKX5 protein in pigment synthesis in the skin and in the eye.