Missing Mutations in Oculocutaneous and Ocular Albinism

描述(申请人提供)：白化病是一组不同类型的遗传性疾病，以黑色素减少或缺失为特征，主要累及眼睛、皮肤和头发。黑色素减少，无论具体的基因缺陷如何，都会导致视束的刻板缺陷，包括中央凹发育不良，从颞叶视网膜到视交叉和视核的神经元投射的异常交叉，以及虹膜色泽减退。这些缺陷加在一起会导致低视力、眼球震颤、斜视和畏光。白化病有两种主要表型。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。眼白化病(OA)主要累及眼睛，并与三个基因的突变有关：Tyr、OCA2和OA1；前两个基因导致常染色体隐性遗传性眼白化病(AROA)和第三个‘X连锁眼白化病’(OA1)。不同形式的眼皮肤和眼白化病在这些疾病患者中的表现尚不清楚，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中的一个，这使得分析和解释变得复杂。我们收集了一大批患有各种不同类型的OCA和ARA的患者，其中许多人(但不是所有人)已经对TYR和OCA2进行了研究。在这里，我们建议系统地研究这些患者TYR、OCA2、TYRP1和MATP的潜在功能性多态变异和病理突变。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，这些研究将极大地提高对眼皮肤白化病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.