Missing Mutations in Oculocutaneous and Ocular Albinism

描述（由申请人提供）：白化病是一种异质性遗传疾病，其特征是黑色素沉着减少或缺失，主要累及眼睛、皮肤和头发。无论具体的基因缺陷是什么，黑色素的减少都会导致视神经束的典型缺陷，包括中央凹发育不全、从颞视网膜到视交叉和视神经核的神经元投射异常，以及虹膜色素减退。这些缺陷共同导致“低视力”、眼球震颤、斜视和畏光。有两种主要的白化病表型。眼皮肤白化病（OCA）涉及眼睛、皮肤和头发，并与四个基因的突变有关：TYR、OCA2、TYRP1和MATP。眼部白化病（OA）主要涉及眼睛，并与三个基因的突变有关：TYR、OCA2和OA1；前两种导致“常染色体隐性眼白化病”（AROA），第三种导致“x连锁眼白化病”（OA1）。在患有这些疾病的患者中，各种形式的眼皮肤白化病和眼白化病的代表性尚不清楚，主要是因为没有对所有这些基因缺陷的患者群体进行系统研究。此外，在许多患者中只能发现两种等位基因突变中的一种，这使分析和解释变得复杂。我们收集了大量不同类型的OCA和AROA患者，其中许多（但不是全部）已经研究过TYR和OCA2。在这里，我们建议系统地研究这些患者在TYR、OCA2、TYRP1和MATP中潜在的功能多态性变异和病理突变。此外，我们建议通过体外细胞系和体内转基因方法来表征这些基因的转录调控区域，特别是TYR和OCA2，然后我们将在这些调控序列中寻找“缺失”的病理突变。总之，这些研究应该大大提高了对皮肤白化病和眼部白化病的分子发病机制的理解。

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.