PDF(Pubmed)
Abstract：
Hypermobile Ehlers-Danlos syndrome (hEDS) is a common heritable connective tissue disorder that lacks a known genetic etiology. To identify genetic contributions to hEDS, whole exome sequencing was performed on families and a cohort of sporadic hEDS patients. A missense variant in Kallikrein-15 (KLK15 p. Gly226Asp), segregated with disease in two families and genetic burden analyses of 197 sporadic hEDS patients revealed enrichment of variants within the Kallikrein gene family. To validate pathogenicity, the variant identified in familial studies was used to generate knock-in mice. Consistent with our clinical cohort, Klk15 G224D/+ mice displayed structural and functional connective tissue defects within multiple organ systems. These findings support Kallikrein gene variants in the pathogenesis of hEDS and represent an important step towards earlier diagnosis and better clinical outcomes.
摘要：
HypermobileEhlers-Danlos综合征（hEDS）是一种常见的遗传性结缔组织疾病，缺乏已知的遗传病因。为了确定对hEDS的遗传贡献，对家庭和一组散发性hEDS患者进行了全外显子组测序.激肽释放酶15的错义变体（KLK15p。Gly226Asp），在两个家庭中与疾病隔离，对197例散发性hEDS患者的遗传负担分析显示，激肽释放酶基因家族中变异的富集。为了验证致病性，在家族研究中鉴定的变异体被用于产生敲入小鼠.与我们的临床队列一致，Klk15G224D/+小鼠在多器官系统内显示结构和功能结缔组织缺陷。这些发现支持激肽释放酶基因变异在hEDS发病机制中的作用，代表了早期诊断和更好临床结果的重要一步。
