Dissection of the Molecular Basis of Pleiotropy Between GnRH Neuronal Development and Cranial Suture Fusion

GnRH 神经元发育与颅缝融合之间多效性的分子基础剖析

基本信息

批准号：
10670359
负责人：
Ravikumar Balasubramanian
金额：
$ 77.29万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670359
关键词：
Affect Alleles Animal Disease Models Atlases Biological Biology Cartilage Clinical Complement Complex Congenital Abnormality Craniosynostosis Data Data Set Defect Development Disease Dissection Embryo Ephrins Erinaceidae FGFR1 gene Fibroblast Growth Factor GLI3 gene Genes Genetic Genetic Diseases Genetic Predisposition to Disease Genomics Genotype Goals Gonadotropin Hormone Releasing Hormone Health Human Human Genetics Hypothalamic structure Idiopathic Hypogonadotropic Hypogonadism Individual Joint structure of suture of skull Link Maps Mendelian disorder Modeling Molecular Mutation Neurons Overlapping Genes Pathogenesis Pathogenicity Pathway interactions Phenotype Population Precision therapeutics Prevalence Proteins Reporting Reproduction Reproductive Endocrinology Research Personnel SOX11 gene Signal Transduction Surgical sutures TWIST1 gene Testing Tissues Transcript Transgenic Organisms Tretinoin Validation Variant Work Zebrafish biobank cartilage cell causal variant cell type clinical care clinical investigation cohort comorbidity craniofacial craniofacial development cranium developmental genetics differential expression gain of function genetic architecture genetic variant human disease human tissue loss of function loss of function mutation migration mutant mutation carrier neurogenesis neuron development novel optimal treatments personalized genomic medicine phenome phenomics pleiotropism premature prospective rare variant reproductive system disorder segregation suture fusion trait transcription factor transcriptomics

项目摘要

PROJECT ABSTRACT Pleiotropy is defined as the phenomenon in which one gene affects multiple distinct phenotypic features. Although unbiased genomic analyses have unmasked its increasing prevalence in Mendelian and complex traits, the full extent of pleiotropy and its molecular basis in humans remains elusive. In this proposal, we will leverage two seemingly distinct developmental genetic conditions, Idiopathic Hypogonadotropic Hypogonadism (IHH) and Craniosynostosis (CS), as hallmark examples to study pleiotropy. IHH is a rare reproductive disorder caused by defective embryonic migration and/or secretion of hypothalamic Gonadotropin-releasing hormone (GnRH) neurons. CS is a birth defect impacting craniofacial development in which one or more of the sutures of the skull fuse prematurely. Several molecular cascades (e.g., FGF, Wnt, BMP, hedgehog, ephrin, and retinoic acid signaling) are known to overlap during GnRH neurogenesis and vertebrate cranial suture fusion. Yet, in humans, shared genetic etiology between IHH and CS has not been widely reported, with only recent appreciation of a partial genetic overlap. Loss-of-function (LOF) FGFR1 mutations cause IHH, while gain-of-function FGFR1 mutations result in CS, offering a plausible underpinning for this pleiotropic observation (opposing variant directional effect). By contrast, LOF mutations in TCF12 (encoding a pro-neural transcription factor) have been shown previously to cause coronal CS in humans, and recently, we identified LOF TCF12 mutations as a novel cause of IHH. Notably, we observed phenotypic co-occurrence of IHH and CS in TCF12 mutation carriers, providing compelling evidence for developmental pleiotropy between IHH and CS. Building on these observations, and the still largely unexplained biologic basis of IHH/CS pleiotropy, the overarching goal of this proposal is to unravel the ensemble of shared molecular pathways that coregulate GnRH and cranial suture development. Our strong investigative team, with complementary expertise in reproductive endocrinology, craniofacial biology, human genetics, animal models of disease, and human clinical investigation will juxtapose human studies (Mendelian disease and population cohorts) with relevant zebrafish models in three distinct Aims: (1) We will define the shared molecular pathways between GnRH neurogenesis and cranial suture fusion using genomic studies in human Mendelian cohorts with validation in transgenic zebrafish; (2) We will utilize differential transcriptomic atlases from human cranial suture and relevant zebrafish GnRH and cartilage cell types to discover novel genes for IHH and CS; and (3) We will utilize population biobanks, IHH, and CS cohorts to define the full extent of phenotypic pleiotropy relating to genes linked to both traits. Defining the underlying mechanisms of pleiotropy for CS and IHH will serve as a blueprint to elucidate further the genetic architecture of human diseases; chart precise genotype-phenotype maps in Mendelian conditions and in population settings; and inform precision therapies for optimal clinical care.

项目摘要多效性被定义为一个基因影响多个不同表型特征的现象。尽管无偏见的基因组分析揭示了其在孟德尔和复杂性状中日益流行，多效性的全部范围及其在人类中的分子基础仍然难以捉摸。在本提案中，我们将利用两种看似不同的发育遗传病，特发性性腺功能减退症 (IHH) 和颅缝早闭（CS），作为研究多效性的标志性例子。 IHH 是一种罕见的生殖疾病，由以下原因引起：胚胎迁移和/或下丘脑促性腺激素释放激素 (GnRH) 分泌缺陷神经元。 CS 是一种影响颅面发育的出生缺陷，其中颅骨的一个或多个缝线过早熔断。多种分子级联（例如 FGF、Wnt、BMP、hedgehog、肝配蛋白和视黄酸已知 GnRH 神经发生和脊椎动物颅缝融合过程中存在重叠。然而，在人类身上， IHH 和 CS 之间共有的遗传病因尚未得到广泛报道，只是最近才认识到部分基因重叠。功能丧失 (LOF) FGFR1 突变会导致 IHH，而功能获得性 FGFR1 突变会导致 IHH 突变导致 CS，为这种多效性观察提供了合理的基础（相反的变异方向效应）。相比之下，TCF12（编码前神经转录因子）的 LOF 突变已被证实之前已显示会导致人类冠状部 CS，最近，我们将 LOF TCF12 突变确定为一种新的突变 IHH 的原因。值得注意的是，我们观察到 IHH 和 CS 在 TCF12 突变携带者中同时出现，为 IHH 和 CS 之间的发育多效性提供令人信服的证据。在此基础上观察结果，以及 IHH/CS 多效性的生物学基础仍然很大程度上无法解释，这是本研究的总体目标提议是解开共同调节 GnRH 和颅缝的共享分子途径的集合发展。我们强大的研究团队在生殖内分泌学方面具有互补的专业知识，颅面生物学、人类遗传学、疾病动物模型和人类临床研究将并列人类研究（孟德尔疾病和群体队列）与相关斑马鱼模型的三个不同目标： (1) 我们将使用以下方法定义 GnRH 神经发生和颅缝融合之间的共享分子途径人类孟德尔队列的基因组研究并在转基因斑马鱼中进行验证； (2)我们将利用微分来自人类颅缝和相关斑马鱼 GnRH 和软骨细胞类型的转录组图谱发现 IHH 和 CS 的新基因； (3) 我们将利用人口生物库、IHH 和 CS 队列来定义与这两个性状相关的基因相关的表型多效性的全部范围。定义底层机制 CS和IHH的多效性将作为进一步阐明人类遗传结构的蓝图疾病；在孟德尔条件和人群环境中绘制精确的基因型-表型图；并告知精准治疗，实现最佳临床护理。