Molecular Genetics of nonsyndromic Oculocutaneous Albinism

描述（由申请人提供）：黑素细胞的许多基本组分的分子特性以及黑素生成和黑素合成的途径仍然未知，在科学界对色素沉着和色素性疾病的组成和机制的完整理解中留下了空白。眼皮肤白化病（OCA）是美国儿童视力损害的主要原因之一。临床上，OCA表现为皮肤、毛发、虹膜和视网膜色素上皮的色素减退、中心凹发育不全、感光杆细胞缺陷、视神经在交叉处的走错、恐惧症和眼球震颤。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必要的，足以引起非综合征型OCA。非综合征型OCA基因的多态性也会增加皮肤癌的易感性。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沉着病的机制，并开发治疗药物用于治疗和预防OCA。本申请的目的是鉴定和表征OCA的四种新的遗传决定因素。我们的假设是，如果一个突变的基因导致色素沉着的损失，那么该基因的正常功能将是必要的正常黑色素细胞和/或黑色素合成。这项研究的基本原理是，确定OCA的所有致病基因并了解其正常功能对于预防色素沉着损失以及由此导致的视力丧失至关重要 和潜在的皮肤癌，以及开发治疗这些损伤的治疗剂。因此，拟议中的研究与NIH的使命的一部分有关，该使命涉及开发可能有助于减轻人类残疾负担的基础知识。在强有力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。具体而言，拟议的实验设计包括：使用大规模平行测序鉴定四个基因，斑马鱼胚胎中新OCA蛋白的功能评价，小鼠神经嵴成黑色素细胞和表皮及视网膜色素上皮黑色素细胞中的表达研究，以及美国人群中致病等位基因的鉴定。拟议的研究将采用当代人类和斑马鱼的遗传、分子、生物化学、心理物理和细胞生物学技术。这项工作是创新的，因为它源于绘制四个新的OCA基因座的初步数据，这代表了目前已知的六个基因的显着增加。这项工作也是创新的，它使用先进的技术相结合，以确定和功能表征四个新的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充分理解和有效治疗人类色素沉着疾病提供分子见解。这项工作的结果具有很大的临床意义 相关性，具有改善色素性疾病的分子流行病学和帮助遗传诊断和咨询的潜力。

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.