首页> 外文期刊>Human Molecular Genetics >Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development
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Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development

机译:歌舞uki综合征基因KMT2D和KDM6A:功能分析表明在颅面,心脏和大脑发育中的关键作用

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摘要

Kabuki syndrome (KS) is a rare multiple congenital anomaly syndrome characterized by distinctive facial features, global developmental delay, intellectual disability and cardiovascular and musculoskeletal abnormalities. While mutations in KMT2D have been identified in a majority of KS patients, a fewpatients have mutations in KDM6A. We analyzed 40 individuals clinically diagnosed with KS for mutations in KMT2D and KDM6A. Mutations were detected in KMT2D in 12 and KDM6A in 4 cases, respectively. Observed mutations included single-nucleotide variations and indels leading to frame shifts, nonsense, missense or splice-site alterations. In two cases, we discovered overlapping chromosome X microdeletions containing KDM6A. To further elucidate the functional roles of KMT2D and KDM6A, we knocked down the expression of their orthologs in zebrafish. Following knockdown of kmt2d and the two zebrafish paralogs kdm6a and kdm6al, we analyzed morphants for developmental abnormalities in tissues that are affected in individuals with KS, including craniofacial structures, heart and brain. The kmt2d morphants exhibited severe abnormalities in all tissues examined. Although the kdm6a and kdm6al morphants had similar brain abnormalities, kdm6a morphants exhibited craniofacial phenotypes, whereas kdm6al morphants had prominent defects in heart development. Our results provide further support for the similar roles of KMT2D and KDM6A in the etiology of KS by using a vertebrate model organism to provide direct evidence of their roles in the development of organs and tissues affected in KS patients.
机译:歌舞uki综合征(KS)是一种罕见的多发性先天性异常综合征,其特征是独特的面部特征,整体发育迟缓,智力残疾以及心血管和肌肉骨骼异常。虽然在大多数KS患者中已发现KMT2D突变,但少数患者的KDM6A突变。我们分析了40名临床确诊为KS的个体的KMT2D和KDM6A突变。分别在12例和4例KDM6A中检测到突变。观察到的突变包括单核苷酸变异和插入缺失,从而导致移码,无意义,错义或剪接位点改变。在两种情况下,我们发现了包含KDM6A的X染色体重叠微缺失。为了进一步阐明KMT2D和KDM6A的功能作用,我们敲低了它们在斑马鱼中的直系同源物的表达。敲低kmt2d以及两个斑马鱼同源物kdm6a和kdm6al之后,我们分析了吗啡酮对受KS感染的个体(包括颅面结构,心脏和大脑)影响的组织中的发育异常。 kmt2d morphant在所有检查的组织中均表现出严重异常。尽管kdm6a和kdm6al修饰物具有相似的脑异常,但kdm6a修饰物表现出颅面表型,而kdm6al修饰物在心脏发育中具有明显的缺陷。我们的结果通过使用脊椎动物模型生物体提供了它们在KS患者受影响的器官和组织发育中的作用的直接证据,为KMT2D和KDM6A在KS病因中的相似作用提供了进一步的支持。

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