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.

项目摘要外显/基因组测序的最新进展导致鉴定涉及的许多新基因在先天性人类疾病中。但是，多皮特这个进步，许多家庭仍然没有收到通用诊断。对于受复杂条件影响的家庭而言，这特别困难疾病管理和生活计划尤其挑战。识别潜在的遗传原因允许这些复杂表型更好地类别，识别常见和可变特征，以及研究疾病机制的倡议。我们最近确定了一个新的因素WDR37，是随意的一个复杂的综合征表型，包括彼得异常和眼睛的角色，身材矮小，全球发育延迟，小头畸形，癫痫发作和心脏缺陷。该基因的功能目前未知没有在人类或动物模型中进行的分析。在此探索性建议中，我们计划执行研究为了更好地理解与WDR37缺乏相关的表型光谱，开发斑马鱼模型在该基因中携带类似人类的变体，并获得对其胚胎功能的首次见解。具体来说，我们计划1）通过对人类的分析来定义WDR37/WDR37在脊椎动物发育和人类疾病中的作用患者和斑马鱼线携带类似人类疾病的变体和2）确定功能 WDR37/WDR37因子的作用，通过分析人类细胞培养中的野生型和突变构建体和斑马鱼模型在WDR37中带有错义和功能丧失变体。这些研究将提供第一个有关WDR37功能和相关先天缺陷的频谱的数据。除此之外，我们的进步了解先天性综合征的机制将导致对人类胚胎的新见解开发，可能会为医疗干预和治疗提供新的目标。