Genetic Basis of Congenital Anophthalmia

先天性无眼症的遗传基础

基本信息

批准号：
8240499
负责人：
Thomas M. Glaser
金额：
$ 34.76万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8240499
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-Box Head Health 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 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 relating to nervous system research study sex trait transcription factor

项目摘要

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.

描述（由申请人提供）：自然情绪，微观心脏和古罗巴马（MAC）是眼睛不存在或很小的出生缺陷，或者在视觉杯发育过程中脉络膜裂缝未能关闭。大多数情况是零星的，但是已经描述了常染色体隐性，占主导地位和X连锁的遗传模式，通常会降低渗透率。已经鉴定出少数基因的突变，包括转录因子PAX6，CHX10，RX，SOX2和OTX2，以及生长因子GDF6和BMP4。这些在建立眼场并扩展视野时表达的。但是，大多数情况仍然无法解释。我们通过大型血统中的链接分析为常染色体显性MAC定义了一个新的基因座。我们旨在完善地图位置并确定非重组区域内的因果突变。我们还发现了患有严重双侧微观心脏或性质的儿童的PAX6和SOX基因重排的新类别。我们的目的是详细表征这些突变，测试发病机理的机理，并系统地筛选范围内MAC患者的同类群体中的整个基因组中的相关突变。最后，我们定义了三个小鼠无眼突变的修饰符（EY1），这是RX同源基因中隐性肌肌倍增等位基因，可降低ZRDCT菌株中RX多肽的丰度，从而产生灵敏的背景，以识别该动物模型中的其他MAC基因（Tucker等人2001）。这些修饰剂基因座（EY2，EY3，EY4）对于表达发病的性质性状是必需的，并在F2交叉中表现出强烈的成对相互作用。已经鉴定出位置候选基因，其中包括腹侧视觉杯形态发生的一种，以及Wnt信号通路的两个拮抗剂，已知可以限制后生动物的眼场。我们提出这些修饰符通过增加头外胚层内的Wnt活性来增强无眼性状的外观。我们旨在完善EY2-EY4的映射，并使用特定的靶向突变和条件敲除小鼠检验该假设。