Gensemer Cortney, Petrucci Taylor, Beck Tyler, Daylor Victoria, Griggs Molly, Griggs Charlotte, Weintraub Amy, Byerly Kathryn, Guo Lilong, Morningstar Jordan, Kornblau Isabelle, Biggs Rachel, Moore Kelsey, Koren Natalie, 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, 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, Kontorovich Amy R, Berrandou Takiy-Eddine, Slaugenhaupt Susan A, Milan David, Maitland Anne, Patel Sunil, Bouatia-Naji Nabila, Norris Russell A
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Department of Neurosurgery, Medical University of South Carolina, Charleston, SC 29407, USA.
iScience. 2025 Aug 12;28(9):113343. doi: 10.1016/j.isci.2025.113343. eCollection 2025 Sep 19.
Hypermobile Ehlers-Danlos syndrome (hEDS) is a debilitating multisystem condition characterized by joint hypermobility, chronic pain, and diverse comorbidities, yet its genetic basis remains undefined. Whole-exome sequencing (WES) of 200 patients with hEDS revealed rare and low frequency variants in 14 of 15 kallikrein (KLK) genes, including a recurrent KLK15 missense variant (p.Gly226Asp) segregating in multiple families. KLK15, a secreted serine protease, is expressed in connective and immune tissues and interacts with extracellular matrix (ECM) components, including fibronectin and lysyl oxidase (LOX). A KLK15 knock-in mouse model recapitulated hEDS features in tendons and cardiac valves and exhibited dysregulated cytokine profiles. The variant altered KLK15 and LOX compartmentalization within the ECM, consistent with a dominant-negative effect. These findings identify KLK15 as a contributor to hEDS and reveal broader roles for KLK protease-ECM-immune crosstalk in connective tissue regulation. This study reframes hEDS as a condition involving matrix remodeling and immune signaling beyond collagen defects.
过度活动型埃勒斯-当洛综合征（hEDS）是一种使人衰弱的多系统疾病，其特征为关节过度活动、慢性疼痛和多种合并症，但其遗传基础仍不明确。对200例hEDS患者进行的全外显子组测序（WES）显示，15种激肽释放酶（KLK）基因中的14种存在罕见和低频变异，包括一个在多个家族中分离的复发性KLK15错义变异（p.Gly226Asp）。KLK15是一种分泌型丝氨酸蛋白酶，在结缔组织和免疫组织中表达，并与细胞外基质（ECM）成分相互作用，包括纤连蛋白和赖氨酰氧化酶（LOX）。一个KLK15基因敲入小鼠模型在肌腱和心脏瓣膜中重现了hEDS的特征，并表现出细胞因子谱失调。该变异改变了ECM内KLK15和LOX的分隔，与显性负效应一致。这些发现确定KLK15是hEDS的一个致病因素，并揭示了KLK蛋白酶-ECM-免疫串扰在结缔组织调节中的更广泛作用。这项研究将hEDS重新定义为一种涉及基质重塑和免疫信号传导而非胶原蛋白缺陷的疾病。
