Molecular Genetics of nonsyndromic Oculocutaneous Albinism

描述（由申请人提供）：黑素细胞的许多基本成分的分子特征以及黑素形成和黑色素合成的途径仍然未知，科学界对色素沉着和色素紊乱的构成和机制的完整理解存在空白。在美国，皮肤白化病（OCA）是儿童视力受损的主要原因之一。临床表现为皮肤、毛发、虹膜、视网膜色素上皮色素减退，中央凹发育不全，光受体杆状细胞缺损，视交叉处视神经走错路，畏光，眼球震颤。目前，至少有18个基因座的突变与OCA有因果关系，6个基因座的遗传缺陷已被证明是引起非综合征性OCA的必要和充分条件。非综合征性OCA基因的多态性也会增加患皮肤癌的易感性。然而，已知的位点/基因并不能解释所有的OCA病例，这强烈表明其他的位点/基因尚未被发现。本研究的长期目标是充分了解遗传性色素紊乱的机制，并开发治疗和预防OCA的药物。这个特殊应用的目的是鉴定和表征四种新的OCA遗传决定因素。我们的假设是，如果一个突变的基因导致色素沉着丧失，那么该基因的正常功能将是正常黑色素细胞和/或黑色素合成所必需的。提出这项研究的基本原理是，确定所有引起OCA的基因并了解它们的正常功能对于预防色素沉着丧失以及由此导致的视力丧失至关重要

DESCRIPTION (provided by applicant): The molecular identities of many essential components of melanocytes and the pathways of melanogenesis and melanin synthesis are still unknown, leaving a gap in the scientific community's complete understanding of the makeup and mechanisms of pigmentation and pigmentary disorders. Oculocutaneous albinism (OCA) represents one of the major causes of childhood vision impairment in United States. Clinically, OCA is manifested by hypopigmentation of skin, hair, iris and retinal pigment epithelium, foveal hypoplasia, photoreceptor rod cell deficit, misrouting of the optic nerves at the chiasm, photophobia and nystagmus. At present, mutations in at least 18 loci have been causally linked with OCA, and genetic defects at six loci have been shown to be necessary and sufficient to cause nonsyndromic OCA. Polymorphisms in the nonsyndromic OCA genes also increase susceptibility for skin cancer. However, the known loci/genes do not account for all cases of OCA, which strongly suggests that other loci/genes have yet to be found. The long-term goal of this research is to fully understand the mechanisms of inherited pigmentary disorders and to develop therapeutic agents for the treatment and prevention of OCA. The objective of this particular application is to identify and characterize four novel genetic determinants of OCA. Our hypothesis is that if a mutated gene causes loss of pigmentation, then the normal function of that gene will be necessary for normal melanocytes and/or melanin synthesis. The rationale for the proposed research is that identifying all causative genes for OCA and understanding their normal function is essential for preventing pigmentation loss, as well as the resulting vision loss and potential skin cancer, and for the development of therapeutic agents to treat these impairments. Thus, the proposed research is relevant to that part of NIH's mission that pertains to developing fundamental knowledge that will potentially help to reduce the burdens of human disability. Guided by strong preliminary data, we will test our hypothesis through identification and evaluation of four novel OCA genes. Specifically, the proposed experimental design includes: identification of four genes using massive parallel sequencing, functional evaluation of new OCA proteins in zebrafish embryos, expression studies in the mouse neural crest melanoblasts and in the epidermal and retinal pigment epithelium melanocytes and identification of pathogenic alleles in the US population. The proposed studies will employ contemporary human and zebrafish genetic, molecular, biochemical, psychophysical and cell biology techniques. The proposed work is innovative, as it stems from preliminary data mapping four new OCA loci, which represent a significant increase from the six currently known genes. This work is also innovative in its use of combination of advanced technologies to identify and functionally characterize four novel OCA genes. The proposed research is significant because the completion of these studies will provide molecular insights to fully understanding and being able to effectively treat pigmentation disorder in humans. Results of this work hold great clinical relevance, with the potential to improve the molecular epidemiology of pigmentary disorders and aid in genetic diagnosis and counseling.