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

• 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
• 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

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 多效性是指一个基因影响多个不同的表型特征的现象。 尽管无偏见的基因组分析揭示了它在孟德尔和复杂性状中的日益普遍性， 人类多效性的完整程度及其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疾病，特发性低促性腺激素性性腺功能减退症（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， 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合线 过早融合几个分子级联（例如，FGF、Wnt、BMP、hedgehog、肝配蛋白和维甲酸 信号）已知在GnRH神经发生和脊椎动物颅缝融合期间重叠。然而，在人类中， IHH和CS之间共有的遗传病因尚未被广泛报道， 部分遗传重叠功能丧失型（LOF）FGFR 1突变导致IHH，而功能获得型FGFR 1突变导致IHH。 突变导致CS，为这种多效性观察提供了合理的基础（相反的变体 方向效应）。相比之下，TCF 12（编码前神经转录因子）中的LOF突变已经被发现。 以前显示在人类中引起冠状CS，最近，我们确定LOF TCF 12突变是一种新的 因为IHH。值得注意的是，我们观察到TCF 12突变携带者中IHH和CS的表型共存， 为IHH和CS之间的发育多效性提供了令人信服的证据。根据这些 观察，以及IHH/CS多效性的生物学基础仍然在很大程度上无法解释，这一研究的总体目标是 一个提议是解开共同调节GnRH和颅缝的分子通路的整体 发展我们强大的调查团队，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、疾病的动物模型和人类临床研究将并列 人类研究（孟德尔疾病和人群队列）与相关的斑马鱼模型在三个不同的目的： (1)我们将使用以下方法来确定GnRH神经发生和颅缝融合之间共有的分子途径： 在人类孟德尔群体中进行基因组研究，并在转基因斑马鱼中进行验证;（2）我们将利用差异 人颅缝转录组图谱和相关斑马鱼GnRH和软骨细胞类型， 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的表型多效性的全部程度。界定基本机制 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;在孟德尔条件下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。