Genetic Basis of Congenital Anophthalmia

描述(由申请人提供)：无眼症、小眼炎和眼球缺陷症(MAC)是指在视杯发育过程中眼睛缺失或非常小，或脉络膜裂隙未能闭合的出生缺陷。大多数病例是零星的，但常染色体隐性遗传、显性遗传和X连锁遗传模式已被描述，通常外显性降低。已发现少数基因发生突变，包括转录因子PAX6、CHX10、RX、SOX2和OTX2，以及生长因子GDF6和BMP4。这些都是在发育的关键早期阶段表达的，此时眼场建立，视原基扩大。然而，大多数案件仍未得到解释。我们在一个大的家系中通过连锁分析确定了常染色体显性遗传MAC的一个新的基因座。我们的目标是改进MAP的位置，并识别非重组区内的致病突变。我们还在严重的双眼小眼炎或无眼症儿童中发现了新的PAX6和SOX基因重排类型。我们的目标是详细描述这些突变的特征，测试发病机制，并系统地筛选全基因组范围的MAC患者队列中的相关突变。最后，我们定义了小鼠盲目突变(Ey1)的三个修饰物，yy1是Rx同源盒基因中的一种隐性亚型等位基因，它降低了ZRDCT菌株中Rx多肽的丰度，创造了一个敏化的背景来确定该动物模型中的其他MAC基因(Tucker等人。2001)。这些修饰基因座(ey2、ey3、ey4)是表达无眼症性状所必需的，并且在F2杂交中表现出很强的成对交互作用。已经确定了位置候选基因，包括腹侧视杯形态发生所需的一个基因，以及两个Wnt信号通路的拮抗剂，该信号通路已知限制后生动物的视场。我们认为，这些修饰剂通过增加头部外胚层中Wnt的活性来增强无眼性状的外显率。我们的目标是改进ey2-ey4的图谱，并使用特定的靶向突变和条件性基因敲除小鼠来测试这一假设。与公共卫生相关：我们将发现导致出生时眼睛缺失(无眼症)、非常小或严重畸形(缺陷症)的突变。我们将使用遗传连锁分析来测试有多个患病儿童的家系，并将确定这些疾病的分子基础。我们还将在实验室小鼠身上测试产生盲目特征的特定基因交互作用。这些研究探索了眼睛形成的最早步骤。我们的结果将提高对人类眼睛畸形以及导致出生缺陷的复杂遗传因素的诊断和理解。

DESCRIPTION (provided by applicant): Anophthalmia, microphthalmia and coloboma (MAC) are birth defects in which the eyes are absent or very small, or where the choroid fissure fails to close during optic cup development. Most cases are sporadic, but autosomal recessive, dominant and X-linked inheritance patterns have been described, often with reduced penetrance. Mutations in few genes have been identified, including transcription factors PAX6, CHX10, RX, SOX2 and OTX2, and growth factors GDF6 and BMP4. These are expressed during critical early stages of development, when the eye field is established and the optic primordia expands. However, most cases remain unexplained. We have defined a new locus for autosomal dominant MAC by linkage analysis in a large pedigree. We aim to refine the map position and identify the causative mutation within the nonrecombinant region. We have also discovered new categories of PAX6 and SOX gene rearrangements in children with severe bilateral microphthalmia or anophthalmia. We aim to characterize these mutations in detail, test the mechanism of pathogenesis, and systematically screen a cohort of MAC patients genome-wide for related mutations. Finally, we have defined three modifiers of the mouse eyeless mutation (ey1), a recessive hypomorphic allele in the Rx homeobox gene that decreases abundance of the Rx polypeptide in the ZRDCT strain, creating a sensitized background to identify additional MAC genes in this animal model (Tucker et al. 2001). These modifier loci (ey2, ey3, ey4) are necessary for expression of the anophthalmia trait and exhibit strong pairwise interactions in an F2 cross. Positional candidate genes have been identified, including one required for morphogenesis of the ventral optic cup, and two antagonists of the Wnt signaling pathway, which is known to restrict the eye field in metazoans. We propose these modifiers enhance penetrance of the eyeless trait by increasing Wnt activity within head ectoderm. We aim to refine the mapping of ey2-ey4, and test this hypothesis using specific targeted mutations and conditional knockout mice. PUBLIC HEALTH RELEVANCE: We will find mutations that cause the eyes to be absent (anophthalmia), very small or severely malformed (coloboma) at birth. We will use genetic linkage analysis to test pedigrees with multiple affected children, and will determine the molecular basis of these disorders. We will also test specific gene interactions that produce an eyeless trait in laboratory mice. These studies explore the earliest steps in eye formation. Our results will improve diagnosis and understanding of human eye malformations, and the complex genetic factors underlying birth defects.