WDR37: a novel factor in human congenital multisystem disease

WDR37：人类先天性多系统疾病的新因素

基本信息

批准号：
9980441
负责人：
Elena V Semina
金额：
$ 22.8万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-20 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980441
关键词：
Address Affect Alleles Amino Acids Animal Model Anterior eyeball segment structure Biogenesis Blindness CRISPR/Cas technology Cell Culture Techniques Cell Cycle Progression Cell Nucleus Chronic Kidney Failure Clinical Management Coloboma Complex Congenital Abnormality Data Defect Degenerative polyarthritis Development Developmental Delay Disorders Dideoxy Chain Termination DNA Sequencing Disease Disease Management Embryo Embryonic Development Eye Face Factor Analysis Family Genes Genetic Genitourinary system Glucosyltransferase Heart Heart Abnormalities Human Human Cell Line Impaired cognition Intervention Irido-corneo-trabecular dysgenesis Knowledge Krause-Kivlin syndrome Lead Life Life Expectancy Medical Microcephaly Modeling Molecular Mosaicism N-terminal Names Pathogenicity Patients Phenotype Positioning Attribute Process Proteins PubMed Publications Rattus Recurrence Reporting Ribosomes Risk Role Seizures Syndrome System Testing Triad Acrylic Resin Variant WD Repeat Zebrafish base exome exome sequencing experimental study gene function genetic disorder diagnosis genetic variant genome editing genome sequencing human disease human model improved insight loss of function malformation mutant next generation novel novel diagnostics offspring response tool transcriptome transcriptome sequencing

项目摘要

Project Summary Recent advances in exome/genome sequencing resulted in the identification of numerous novel genes involved in congenital human disorders. However, despite this progress, many families still do not receive a genetic diagnosis. This is particularly difficult for families affected by complex conditions ‘without a name’ making their disease management and life planning especially challenging. Identification of an underlying genetic cause allows for better categorization of these complex phenotypes, identification of common and variable features, and initiation of studies into disease mechanisms. We recently identified a novel factor, WDR37, as causative in a complex syndromic phenotype including Peters anomaly and coloboma of the eye, short stature, global developmental delay, microcephaly, seizures, and heart defects. The function of this gene is currently unknown with no analyses performed in humans or animal models. In this exploratory proposal, we plan to execute studies to better understand the phenotypic spectrum associated with WDR37 deficiency, develop zebrafish models carrying human-like variants in this gene, and gain the first insights into its embryonic function. Specifically, we plan 1) to define the role of WDR37/wdr37 in vertebrate development and human disease by analyses of human patients and zebrafish lines carrying human-like disease- associated variants and 2) to determine the functional role(s) of WDR37/wdr37 factors by analysis of wild-type and mutant constructs in human cell culture and zebrafish model carrying missense and loss-of-function variants in wdr37. These studies will provide the first data regarding WDR37 function and the spectrum of associated birth defects. In addition to this, our improved understanding of the mechanisms of congenital syndromes will lead to new insights into human embryonic development and is likely to provide new targets for medical intervention and treatment.

项目概要外显子组/基因组测序的最新进展导致了许多涉及的新基因的鉴定然而，尽管取得了这些进展，许多家庭仍然没有获得遗传基因。对于受到“无名”复杂情况影响的家庭来说，诊断尤其困难。疾病管理和生活规划尤其具有挑战性，要确定潜在的遗传原因。可以更好地对这些复杂的表型进行分类，识别共同和可变的特征，并开始研究疾病机制。最近，我们发现了一种新的因素，WDR37，是导致这种疾病的原因。复杂的综合征表型，包括 Peters 异常和眼睛缺损、身材矮小、整体性发育迟缓、小头畸形、癫痫和心脏缺陷该基因的功能目前尚不清楚。在这个探索性提案中，我们计划进行研究，但没有在人类或动物模型中进行分析。为了更好地了解与 WDR37 缺陷相关的表型谱，开发斑马鱼模型在该基因中携带类似人类的变异，并首次了解其胚胎功能。计划1)通过分析人类来定义WDR37/wdr37在脊椎动物发育和人类疾病中的作用携带类人疾病相关变异的患者和斑马鱼系，2) 确定功能通过分析人类细胞培养物中的野生型和突变体构建体来了解 WDR37/wdr37 因子的作用这些研究将提供第一个在 wdr37 中携带错义和功能丧失变异的斑马鱼模型。除此之外，我们还改进了有关 WDR37 功能和相关出生缺陷范围的数据。对先天性综合症机制的了解将为人类胚胎发育带来新的见解的发展，并可能为医疗干预和治疗提供新的目标。