KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome

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.

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Publication Details

Journal
iScience
Published
2025-08-12
DOI
https://doi.org/10.1016/j.isci.2025.113343
Citations
5
Primary Topic
Dermatological and Skeletal Disorders
Type
article
Field-Weighted Citation Impact
9.09

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article

KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome

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5 citations
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article

KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome

Rebecca Byrd, Gyda Beeson, Russell A. Norris, Steven A. Kautz, Rachel Biggs, Clair A. Francomano, Rupak Mukherjee, Jordan Morningstar, Natalie Koren, Kelsey Moore, Alexander Awgulewitsch, David J. Milan, Amy Kontorovich, Anne Maitland, Kristina Stayer, R Price, Nabila Bouatia‐Naji, Jan Guz, Joe Ryan Delaney, Daniel Philip Judge, Tyler Beck, Steven M. Shapiro, Julianna Weninger, Lilong Guo, Takiy-Eddine Berrandou, Susan Slaugenhaupt, Cortney Gensemer, Jason C. Kovacic, Taylor Petrucci, Emily Oberlies, Ella R. Zientara, Elsie Devey, Roman Fenner, Sofia Luzbetak, Erika Bistran, Madalyn Osterhaus, Jillian Schnaudigel, Sydney Severance, Isabelle Kornblau, Peng Chen, Sarah A. Dooley, Fraser C. Henderson, Emily Fleck, Joshua Kerns, Molly Griggs, C. E. Hastings, Shaina Butler, Amy Weintraub, Sunil Patel, Mark E. Lavallee, Hai Yao, Katherine Singleton, Deatra Bear, Charlotte Griggs, Wiley Kendall, Kathryn Byerly, Victoria Daylor BFA
article en
5 citations

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.

iScienceVol. 28(9)
University of Maryland, Baltimore (US), University of Maryland Medical Center (US), Harvard University (US), Medical University of South Carolina (US), Inserm (FR), University of South Carolina (US), Victor Chang Cardiac Research Institute (AU), Aarhus University (DK), Université Paris Cité (FR), Fondation Leducq (FR), Boston Foundation (US), Massachusetts General Hospital (US), The Metropolitan Opera (United States) (US), St Vincent's Clinic (AU), Paris Cardiovascular Research Center (FR), Ralph H. Johnson VA Medical Center (US), University of Pittsburgh Medical Center (US), Center for Systems Biology (US), Indiana University School of Medicine, Indiana University – Purdue University Indianapolis (US), Drexel University (US), Clemson University (US), Icahn School of Medicine at Mount Sinai (US)
American Heart Association, Milton and Tamar Maltz Family Foundation, Fullerton College Foundation, Ehlers-Danlos Society, Ines Mandl Research Foundation, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Dental and Craniofacial Research, National Center for Advancing Translational Sciences, Office of Extramural Research, National Institutes of Health
Openalex Percentile: Top 2%
Dermatological and Skeletal Disorders
9.09
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