Missing Mutations in Oculocutaneous and Ocular Albinism

描述（由申请人提供）：白化病是一组异质性遗传性疾病，其特征是黑色素沉着减少或缺失，主要累及眼睛、皮肤和毛发。无论特定基因缺陷如何，黑色素减少都会导致视神经束的刻板缺陷，包括中央凹发育不全、从颞视网膜到视交叉和视核的神经元投射的异常交叉以及虹膜色素减退。 这些缺陷共同导致“低视力”、眼球震颤、斜视和恐惧症。 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，OCA 2，TYRP 1和MATP。 眼白化病（OA）主要涉及眼睛，并与三个基因的突变有关：TYR，OCA 2和OA 1;前两个导致“常染色体隐性眼白化病”（AROA）和第三个“X连锁眼白化病”（OA 1）。 在患有这些疾病的患者中，各种形式的眼皮肤和眼白化病的表现尚不清楚，主要是因为没有对所有这些基因的缺陷进行系统研究。 此外，在许多患者中，只能发现两个等位基因突变之一，使分析和解释复杂化。 我们已经收集了大量患有各种不同类型OCA和AROA的患者，其中许多（但不是全部）已经进行了TYR和OCA 2研究。 在这里，我们建议系统地研究这些患者潜在的功能多态性变异和病理性突变的TYR，OCA 2，TYRP 1，和MATP。 此外，我们建议通过体外细胞系和体内转基因方法表征这些基因的转录调控区，特别是TYR和OCA 2，然后我们将在这些调控序列中寻找“缺失”的病理突变。 总之，这些研究应该提供了一个大大提高了理解的分子发病机制的眼皮肤和眼白化病。

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.