Genetic Basis of Congenital Anophthalmia

先天性无眼症的遗传基础

• 批准号: 7809496
• 负责人: Thomas M. Glaser
• 金额: $ 36.57万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7809496
• 关键词: 1q41; Accounting; Affect; Alleles; Animal Model; Aniridia; Anophthalmos; Anterior; Aphakia; Autistic Disorder; BMP4; Bilateral; Biochemical; Birth; Blindness; Candidate Disease Gene; Categories; Child; Childhood; Choroid; Chromosomes; Coloboma; Complex; Congenital Abnormality; Copy Number Polymorphism; Crystalline Lens; DNA Sequence Rearrangement; Data; Development; Diagnosis; Disease; Dominant-Negative Mutation; Ectoderm; Epithelium; Etiology; Evolution; Exhibits; Eye; Eye Development; Eye diseases; Failure; Family; Gene Rearrangement; Generations; Genes; Genetic; Genomic Imprinting; Growth Factor; HMG Domain; HMG-Box; Head; Homeobox Genes; Human; Inheritance Patterns; Initiator Codon; Knock-out; Knockout Mice; Knowledge; Laboratory mice; Lens Placodes; Life; Link; Maps; Microphthalmos; Microsatellite Repeats; Modeling; Molecular; Morphogenesis; Multifactorial Inheritance; Mus; Mutant Strains Mice; Mutation; Neural tube; Optic vesicle; Optics; Pathogenesis; Patients; Penetrance; Phenotype; Point Mutation; Positioning Attribute; Prevention; Primordium; Proteins; Regulator Genes; Retina; Retinal; Role; Signal Pathway; Signaling Molecule; Single Nucleotide Polymorphism; Spinal Dysraphism; Staging; Structure of retinal pigment epithelium; Surface; Testing; Vesicle; Visual Fields; Wallerian Degeneration; base; cleft lip and palate; cohort; density; developmental disease; eye formation; gastrulation; gene interaction; genetic linkage analysis; genetic pedigree; genome-wide; growth differentiation factor 6; homeodomain; improved; lens; lens induction; male; malformation; mouse model; optic cup; polypeptide; prenatal; proband; public health relevance; relating to nervous system; research study; sex; trait; transcription factor

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.

描述（由申请人提供）：无眼症、小眼症和缺损 (MAC) 是先天缺陷，其中眼睛缺失或非常小，或者在视杯发育过程中脉络裂无法闭合。大多数病例是散发性的，但常染色体隐性、显性和 X 连锁遗传模式已被描述，通常外显率降低。已发现少数基因突变，包括转录因子 PAX6、CHX10、RX、SOX2 和 OTX2，以及生长因子 GDF6 和 BMP4。这些在发育的关键早期阶段表达，此时眼野已建立且视原基扩张。然而，大多数案件仍然无法解释。我们通过大型谱系的连锁分析，定义了常染色体显性 MAC 的新基因座。我们的目标是完善图谱位置并识别非重组区域内的致病突变。我们还在患有严重双侧小眼症或无眼症的儿童中发现了新类型的 PAX6 和 SOX 基因重排。我们的目标是详细描述这些突变的特征，测试发病机制，并系统地筛查一组 MAC 患者全基因组的相关突变。最后，我们定义了小鼠无眼突变 (ey1) 的三个修饰因子，Rx 同源盒基因中的隐性亚等位基因，可降低 ZRDCT 品系中 Rx 多肽的丰度，从而创建一个敏化背景来识别该动物模型中的其他 MAC 基因 (Tucker et al. 2001)。这些修饰基因座（ey2、ey3、ey4）对于无眼性状的表达是必需的，并且在 F2 杂交中表现出强烈的成对相互作用。位置候选基因已被确定，包括腹侧视杯形态发生所需的一个基因，以及 Wnt 信号通路的两个拮抗剂，已知 Wnt 信号通路会限制后生动物的眼野。我们建议这些修饰剂通过增加头部外胚层内的 Wnt 活性来增强无眼性状的外显率。我们的目标是完善 ey2-ey4 的图谱，并使用特定的靶向突变和条件敲除小鼠来测试这一假设。公共卫生相关性：我们会发现导致出生时眼睛缺失（无眼症）、眼睛非常小或严重畸形（缺损）的突变。我们将使用遗传连锁分析来测试多个受影响儿童的家谱，并确定这些疾病的分子基础。我们还将测试在实验室小鼠中产生无眼特征的特定基因相互作用。这些研究探讨了眼睛形成的最早步骤。我们的研究结果将改善对人眼畸形以及出生缺陷背后的复杂遗传因素的诊断和理解。