Missing Mutations in Oculocutaneous and Ocular Albinism

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Albinism is a heterogeneous group of genetic disorders characterized by reduced or absent melanin pigmentation, mainly involving the eyes, skin, and hair. Reduced melanin, regardless of the specific gene defect, results in stereotypic defects of the optic tracts that include foveal hypoplasia, aberrant decussation of neuronal projections from the temporal retinal to the optic chiasm and optic nuclei, and hypopigmented irides. Together, these defects result in 'low vision', nystagmus, strabismus, and photophobia. There are two principal albinism phenotypes. Oculocutaneous albinism (OCA) involves the eyes, skin and hair, and is associated with mutations in four genes: TYR, OCA2, TYRP1, and MATP. Ocular albinism (OA) involves principally the eyes, and is associated with mutations in three genes: TYR, OCA2, and OA1; the first two result in 'autosomal recessive ocular albinism' (AROA) and the third 'X-linked ocular albinism' (OA1). The representation of the various forms of oculocutaneous and ocular albinism among patients with these disorders is not clear, principally because no groups of patients have been systematically studied for defects in all of these genes. Furthermore, in many patients only one of two allelic mutations can be found, complicating analyses and interpretations. We have assembled a large group of patients with various different types of OCA and AROA, many (but not all) of whom have already been studied for TYR and OCA2. Here, we propose to systematically study these patients for potentially functional polymorphic variants and pathologic mutations in TYR, OCA2, TYRP1, and MATP. Further, we propose to characterize, by in vitro cell line and in vivo transgenic methods, transcriptional regulatory regions of these genes, particularly for TYR and OCA2, and we will then search for 'missing' pathologic mutations in these regulator sequences. Together, these studies should provide a greatly improved understanding of the molecular pathogenesis of oculocutaneous and ocular albinism.