Molecular and Developmental Analysis of Holoprosencephaly

前脑无裂畸形的分子和发育分析

基本信息

批准号：
9306018
负责人：
Robert S. Krauss
金额：
$ 41.63万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9306018
关键词：
Address Alcohols Binding Biochemical Biological Biological Assay CDON gene CFC1 gene Cells Clinical Complement Complex Counseling Defect Development Embryo Environmental Risk Factor Ethanol Etiology Face Failure Fetal Alcohol Exposure Gene Mutation Genes Genetic Genetic Counseling Genetic Heterogeneity Genetic Predisposition to Disease Genotype Histologic Holoprosencephaly Human In Vitro Individual Missense Mutation Modeling Molecular Molecular Analysis Morphology Mus Mutate Mutation Nature Outcome Pathogenicity Pathway interactions Patients Pattern Penetrance Phenotype Preventive Process Prosencephalon Regulation Role SHH gene Series Signal Pathway Signal Transduction Sonic Hedgehog Pathway Specificity Time Variant base craniofacial gastrulation genetic variant in utero insight loss of function mouse model mutation carrier offspring prevent public health relevance receptor smoothened signaling pathway sonic hedgehog receptor

项目摘要

DESCRIPTION (provided by applicant): Holoprosencephaly (HPE) is a common human developmental defect caused by failure to define the midline of the forebrain and/or midface. HPE is associated with heterozygous mutations in NODAL and Sonic hedgehog (SHH) pathway components, but clinical presentation is highly variable, and many mutation carriers are unaffected. It is therefore thought that such mutations must interact with more common modifiers, genetic and/or environmental. Furthermore, many distinct variant alleles are observed for individual HPE-associated genes. HPE is therefore characterized by a lack of clear genotype-phenotype correlation and by high genetic heterogeneity. These phenomena have prevented a deep understanding of HPE etiology and made it difficult to provide counseling to mutation carriers. Two significant issues need to be addressed to provide accurate information: 1) interactions between bona fide pathogenic mutations and the modifiers that grade penetrance and expressivity must be identified and understood mechanistically; and 2) specific HPE-associated genetic variants must be analyzed to prove that they are functionally deficient and identify the underlying mechanism. This proposal addresses both issues. We have modeled HPE in mice. CDON encodes a multifunctional coreceptor that promotes signaling by several pathways, including the SHH pathway. Mice with a mutation in Cdon have a largely subthreshold defect in SHH signaling. These mice are sensitive to induction of a spectrum of craniofacial and forebrain HPE phenotypes by genetic or environmental modifiers that are, themselves, insufficient to produce HPE. Among these modifiers is transient fetal alcohol exposure during gastrulation. New findings indicate that, in addition to its role in SHH signaling, CDON interacts with components of the NODAL receptor complex. Furthermore, transient inhibition of NODAL pathway activity appears to be the point of synergistic interaction between loss of CDON and fetal alcohol exposure. Regulation of NODAL signaling represents a new role for CDON, complementing its function in SHH signaling during midline patterning of the face and forebrain. We have also identified and characterized loss-of-function CDON mutations in human HPE. Other components of the SHH receptor complex are also mutated in human HPE, including PTCH1 and BOC, but there is little information on whether and how these receptor variants are defective in SHH signaling. The following Aims are proposed: 1) to determine genetic and mechanistic interactions between CDON and the NODAL pathway; and 2) to determine the functional and mechanistic consequences of HPE-associated variants in BOC and PTCH1. The successful completion of the proposed aims will provide important information about: 1) how environmental factors interact with predisposing mutations, thus providing a basis for preventive action; and 2) the pathogenic nature of specific patient mutations. Therefore, these studies are expected to aid in the counseling of individuals whose offspring may be genetically predisposed to HPE.

描述（由申请人提供）：前脑无裂畸形（HPE）是一种常见的人类发育缺陷，由于未能界定前脑和/或面中部的中线而引起。 HPE 与 NODAL 和 Sonic hedgehog (SHH) 通路成分的杂合突变有关，但临床表现变化很大，许多突变携带者不受影响。因此，人们认为此类突变必须与更常见的修饰因子、遗传和/或环境相互作用。此外，在各个 HPE 相关基因中观察到许多不同的变异等位基因。因此，HPE 的特点是缺乏明确的基因型-表型相关性和高度遗传异质性。这些现象阻碍了对HPE病因的深入了解，也使得为突变携带者提供咨询变得困难。为了提供准确的信息，需要解决两个重要问题：1）必须从机制上识别和理解真正的致病突变与外显率和表达性分级修饰剂之间的相互作用； 2) 必须分析特定的 HPE 相关遗传变异，以证明它们存在功能缺陷并确定潜在机制。该提案解决了这两个问题。我们在小鼠身上建立了 HPE 模型。 CDON 编码多功能辅助受体，可通过多种途径（包括 SHH 途径）促进信号传导。 Cdon 突变的小鼠在 SHH 信号传导方面存在很大程度上的阈下缺陷。这些小鼠对遗传或环境调节剂诱导一系列颅面和前脑 HPE 表型敏感，而这些调节剂本身不足以产生 HPE。这些修饰因素包括原肠胚形成期间短暂的胎儿酒精暴露。新的研究结果表明，除了在 SHH 信号传导中的作用外， CDON 与 NODAL 受体复合物的成分相互作用。此外，NODAL 通路活性的短暂抑制似乎是 CDON 缺失和胎儿酒精暴露之间协同相互作用的点。 NODAL 信号传导的调节代表了 CDON 的新作用，补充了其在面部和前脑中线模式形成过程中 SHH 信号传导中的功能。我们还鉴定并表征了人类 HPE 中的功能丧失 CDON 突变。 SHH 受体复合物的其他成分在人类 HPE 中也发生突变，包括 PTCH1 和 BOC，但关于这些受体变体在 SHH 信号传导中是否以及如何存在缺陷的信息很少。提出以下目标：1）确定 CDON 和 NODAL 通路之间的遗传和机制相互作用； 2) 确定 BOC 和 PTCH1 中 HPE 相关变异的功能和机制后果。成功完成所提出的目标将提供以下重要信息：1）环境因素如何与易感突变相互作用，从而为预防行动提供基础； 2) 特定患者突变的致病性质。因此，这些研究预计将有助于为其后代可能具有 HPE 遗传倾向的个体提供咨询。