WDR37: a novel factor in human congenital multisystem disease

项目摘要 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 在人类先天疾病中。然而，尽管取得了这一进展，许多家庭仍然没有获得基因 诊断。对于受复杂疾病影响的家庭来说，这尤其困难，因为他们没有名字 疾病管理和生活规划尤其具有挑战性。确定潜在的遗传原因 允许更好地对这些复杂的表型进行分类，识别共同和可变特征， 以及启动对疾病机制的研究。我们最近发现了一种新的因子，WDR37，它是导致 一种复杂的综合征表型，包括眼部彼得斯畸形和缺损，身材矮小，全局性 发育迟缓、小头畸形、癫痫发作和心脏缺陷。该基因的功能目前尚不清楚。 没有在人类或动物模型上进行分析。在这个探索性的提案中，我们计划进行研究 为了更好地了解与WDR37缺乏症相关的表型谱，开发斑马鱼模型 在这个基因中携带与人类相似的变体，并对其胚胎功能获得第一次洞察。具体来说，我们 计划1)通过对人类的分析，确定wdr37/wdr37在脊椎动物发育和人类疾病中的作用 患者和携带类人类疾病相关变异的斑马鱼品系和2)确定功能 野生型和突变型结构分析中wdr37/wdr37因子在人细胞培养中的作用(S) Wdr37中携带错义和功能丧失变体的斑马鱼模型。这些研究将提供第一个 有关WDR37功能和相关出生缺陷谱的数据。除此之外，我们改进了我们的 了解先天性综合征的机制将为人类胚胎带来新的洞察力 发展，并有可能为医疗干预和治疗提供新的目标。

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.