Molecular Genetics of nonsyndromic Oculocutaneous Albinism

描述(申请人提供)：黑素细胞的许多基本成分的分子身份以及黑素生成和黑色素合成的途径尚不清楚，这使得科学界对色素沉着和色素紊乱的组成和机制的全面了解存在空白。眼皮肤白化病(OCA)是美国儿童视力障碍的主要原因之一。临床表现为皮肤、毛发、虹膜及视网膜色素上皮色素沉着，中央凹发育不良，视感受器视杆细胞缺失，视交叉视神经错位，畏光及眼球震颤。目前，至少有18个基因座的突变与OCA有因果关系，有6个基因座的遗传缺陷被证明是导致非综合征性OCA的必要条件和充分条件。非综合征性OCA基因的多态也增加了皮肤癌的易感性。然而，已知的基因座/基因并不能解释所有的OCA病例，这强烈地表明其他的基因座/基因还没有被发现。这项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的治疗药物。这一特殊应用的目的是识别和表征OCA的四个新的遗传决定因素。我们的假设是，如果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的黑素细胞和/或黑色素合成所必需的。这项拟议的研究的基本原理是，确定所有导致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损失至关重要。 和潜在的皮肤癌，以及治疗这些损伤的治疗剂的开发。因此，拟议的研究与NIH使命中与发展基础知识相关的部分相关，这可能有助于减轻人类残疾的负担。在强大的初步数据的指导下，我们将通过鉴定和评估四个新的OCA基因来验证我们的假设。具体地说，建议的实验设计包括：使用大规模平行测序鉴定四个基因，评估斑马鱼胚胎中新的OCA蛋白的功能，研究小鼠神经脊黑素母细胞以及表皮和视网膜色素上皮黑素细胞的表达，以及鉴定美国人群中的致病等位基因。拟议的研究将采用当代人类和斑马鱼的遗传学、分子、生化、心理物理学和细胞生物学技术。这项拟议的工作是创新的，因为它源于定位四个新的OCA基因的初步数据，这些基因比目前已知的六个基因有了显著的增加。这项工作还具有创新性，它结合先进的技术来鉴定和鉴定四个新的OCA基因。这项拟议的研究意义重大，因为这些研究的完成将为全面了解并能够有效治疗人类色素沉着障碍提供分子洞察力。这项工作的结果具有很大的临床意义。 相关性，有可能改善色素紊乱的分子流行病学，并有助于遗传诊断和咨询。

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.