Gensemer, Cortney and Petrucci, Taylor and Beck, Tyler and Daylor, Victoria and Griggs, Molly and Griggs, Charlotte and Weintraub, Amy and Byerly, Kathryn and Guo, Lilong and Morningstar, Jordan and Kornblau, Isabelle and Biggs, Rachel and Moore, Kelsey and Koren, Natalie and Hastings, Christina and Oberlies, Emily and Zientara, Ella R. and Devey, Elsie and Dooley, Sarah and Stayer, Kristina and Fenner, Roman and Singleton, Katherine and Luzbetak, Sofia and Bear, Deatra and Byrd, Rebecca and Weninger, Julianna and Bistran, Erika and Beeson, Gyda and Kerns, Joshua and Osterhaus, Madalyn and Fleck, Emily and Schnaudigel, Jillian and Butler, Shaina and Severance, Sydney and Kendall, Wiley and Delaney, Joe R. and Judge, Daniel P. and Chen, Peng and Yao, Hai and Guz, Jan and Awgulewitsch, Alexander and Kautz, Steven A. and Mukherjee, Rupak and Price, Robert and Henderson, Fraser and Shapiro, Steven and Francomano, Clair A. and Kovacic, Jason C. and Lavallee, Mark and Kontorovich, Amy R. and Berrandou, Takiy-Eddine and Slaugenhaupt, Susan A. and Milan, David and Maitland, Anne and Patel, Sunil and Bouatia-Naji, Nabila and Norris, Russell A. (2025) KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome. iScience, 28 (9). p. 113343. ISSN 25890042
Full text not available from this repository.Abstract
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.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 03 Nov 2025 02:34 |
| Last Modified: | 03 Nov 2025 02:34 |
| URI: | http://eprints.victorchang.edu.au/id/eprint/1741 |
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