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.

项目摘要多效性定义为一种基因影响多种不同表型特征的现象。尽管公正的基因组分析已揭示了其在门德尔和复杂性状中的患病率的增加，但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。在此提案中，我们将利用两种看似不同的发育遗传条件，特发性性腺功能不全的性腺自由度（IHH）和颅骨突变病（CS），作为研究多效性的标志性例子。 IHH是由下丘脑性促性腺激素释放激素（GNRH）的胚胎迁移和/或分泌有缺陷神经元。 CS是影响颅面发育的出生缺陷，其中一个或多个头骨的缝合线过早融合。几个分子级联众所周知，在GNRH神经发生和脊椎动物颅缝合融合过程中，信号传导是重叠的。然而，在人类中 IHH和CS之间共享的遗传病因尚未得到广泛报道，仅最近对部分遗传重叠。功能丧失（LOF）FGFR1突变导致IHH，而功能障碍FGFR1 突变导致CS，为这种多效性观察提供了合理的基础（相反的变体）定向效应）。相比之下，TCF12中的LOF突变（编码促神经转录因子）已是先前显示的是在人类中引起冠状CS，最近，我们将LOF TCF12突变确定为一种新型 IHH的原因。值得注意的是，我们观察到TCF12突变载体中IHH和CS的表型共发生，为IHH和CS之间的发育多效性提供了令人信服的证据。建立在这些基础上观察结果以及IHH/CS多效性的仍然无法解释的生物学基础，这是总体目标建议是揭开共享分子途径的合奏，以促进GNRH和颅骨缝合线发展。我们的强大调查团队，具有生殖内分泌学方面的互补专业知识，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（Mendelian疾病和人群同类）与相关的斑马鱼模型有三个不同的目标：（1）我们将使用使用GNRH神经发生与颅缝合融合之间的共享分子途径人类孟德尔人队列中的基因组研究与转基因斑马鱼中的验证；（2）我们将利用差异来自人类颅骨缝合线和相关斑马鱼GnRH和软骨细胞类型的转录组图谱发现IHH和CS的新颖基因；（3）我们将利用人口生物库，IHH和CS队列来定义与两个性状相关的基因相关的表型多效性的全部程度。定义基本机制 CS和IHH的多效性将作为蓝图，以进一步阐明人类的遗传结构疾病；在门德尔条件和人口设置中，图表精确的基因型 - 表型图；并告知最佳临床护理的精确疗法。