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鉴定了许多涉及的新基因 人类先天性疾病然而，尽管取得了这一进展，许多家庭仍然没有得到遗传学上的帮助。 诊断.这对于受复杂情况影响的家庭来说尤其困难，因为他们没有名字， 疾病管理和生命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， 并开始研究疾病机制。我们最近发现了一个新的因素，WDR 37，作为致病因素， 一种复杂的综合征表型，包括Peters异常和眼缺损、身材矮小、球形 发育迟缓、小头畸形、癫痫和心脏缺陷。这个基因的功能目前尚不清楚 没有在人类或动物模型中进行分析。在这个探索性的建议中，我们计划进行研究， 为了更好地了解与WDR 37缺陷相关的表型谱，开发斑马鱼模型 在这个基因中携带类似人类的变体，并获得对其胚胎功能的第一个见解。我们特别 计划1）通过分析人的WDR 37/wdr 37基因，确定WDR 37/wdr 37在脊椎动物发育和人类疾病中的作用。 患者和携带类人疾病相关变体的斑马鱼系，和2）确定功能性 通过分析人细胞培养物中的野生型和突变体构建体来分析WDR 37/wdr 37因子的作用， 在wdr 37中携带错义和功能丧失变体的斑马鱼模型。这些研究将首次提供 关于WDR 37功能和相关出生缺陷谱的数据。除此之外，我们的改进 了解先天性综合征的机制将导致对人类胚胎发育的新认识。 这可能会为医学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.