激肽释放酶基因家族中的变异与关节过度活动型埃勒斯-当洛综合征
Variants in the Kallikrein Gene Family and Hypermobile Ehlers-Danlos Syndrome.
作者信息
Gensemer Cortney, Beck Tyler, Guo Lilong, Petrucci Taylor, Morningstar Jordan, Kornblau Isabelle, Byerly Kathryn, Biggs Rachel, Weintraub Amy, Moore Kelsey, Koren Natalie, Daylor Victoria, Hastings Christina, Oberlies Emily, Zientara Ella R, Devey Elsie, Dooley Sarah, Stayer Kristina, Fenner Roman, Singleton Katherine, Luzbetak Sofia, Bear Deatra, Byrd Rebecca, Weninger Julianna, Bistran Erika, Beeson Gyda, Kerns Joshua, Griggs Molly, Griggs Charlotte, Osterhaus Madalyn, Fleck Emily, Schnaudigel Jillian, Butler Shaina, Severance Sydney, Kendall Wiley, Delaney Joe R, Judge Daniel P, Chen Peng, Yao Hai, Guz Jan, Awgulewitsch Alexander, Kautz Steven A, Mukherjee Rupak, Price Robert, Henderson Fraser, Shapiro Steven, Francomano Clair A, Kovacic Jason C, Lavallee Mark, Patel Sunil, Berrandou Takiy-Eddine, Slaugenhaupt Susan A, Milan David, Kontorovich Amy R, Bouatia-Naji Nabila, Norris Russell A
机构信息
Medical University of South Carolina.
出版信息
Res Sq. 2024 Jun 10:rs.3.rs-4547888. doi: 10.21203/rs.3.rs-4547888/v1.
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 (KLK15 p. Gly226Asp), segregated with disease in two families and genetic burden analyses of 197 sporadic hEDS patients revealed enrichment of variants within the gene family. To validate pathogenicity, the variant identified in familial studies was used to generate knock-in mice. Consistent with our clinical cohort, mice displayed structural and functional connective tissue defects within multiple organ systems. These findings support gene variants in the pathogenesis of hEDS and represent an important step towards earlier diagnosis and better clinical outcomes.
高活动型埃勒斯-当洛综合征（hEDS）是一种常见的遗传性结缔组织疾病，其遗传病因尚不明确。为了确定hEDS的遗传因素，对多个家族以及一组散发型hEDS患者进行了全外显子组测序。在两个家族中，一个位于KLK15基因（KLK15 p.Gly226Asp）的错义变异与疾病共分离，并且对197例散发型hEDS患者的遗传负担分析显示，该基因家族内的变异出现富集。为了验证致病性，将家族性研究中鉴定出的变异用于构建基因敲入小鼠。与我们的临床队列一致，敲入小鼠在多个器官系统中表现出结构和功能上的结缔组织缺陷。这些发现支持KLK15基因变异在hEDS发病机制中的作用，代表了朝着早期诊断和改善临床结果迈出的重要一步。
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