KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome
Year: 2025
Type: article
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.
Source: iScience
Authors: Cortney Gensemer, Taylor Petrucci, Tyler Beck, Victoria Daylor, Molly Griggs, Charlotte Griggs, Amy Weintraub, Kathryn Byerly, Lilong Guo, Jordan Morningstar, Isabelle Kornblau, Rachel Biggs, Kelsey Moore, Natalie Koren, Christina Hastings, Emily Oberlies, Ella R. Zientara, Elsie Devey, Sarah Dooley, Kristina Stayer, Roman Fenner, Katherine Singleton, Sofia Luzbetak, Deatra Bear, Rebecca Byrd, Julianna Weninger, Erika Bistran, Gyda Beeson, Joshua Kerns, Madalyn Osterhaus, Emily Fleck, Jillian Schnaudigel, Shaina Butler, Sydney Severance, Wiley Kendall, Joe R. Delaney, Daniel P. Judge, Peng Chen, Hai Yao, Jan Guz, Alexander Awgulewitsch, Steven A. Kautz, Rupak Mukherjee, Robert Price, Fraser Henderson, Steven Shapiro, Clair A. Francomano, Jason C. Kovacic, Mark Lavallee, Amy R. Kontorovich, Takiy-Eddine Berrandou, Susan A. Slaugenhaupt, David Milan, Anne Maitland, Sunil Patel, Nabila Bouatia-Naji, Russell A. Norris
Institutions: Medical University of South Carolina, Icahn School of Medicine at Mount Sinai, Clemson University, Ralph H. Johnson VA Medical Center, University of South Carolina, Indiana University School of Medicine, Victor Chang Cardiac Research Institute, University of Pittsburgh Medical Center, Drexel University, Inserm, Aarhus University, Université Paris Cité, Paris Cardiovascular Research Center, Harvard University, Massachusetts General Hospital
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,240
Funders: American Heart Association, Milton and Tamar Maltz Family Foundation, Fullerton College Foundation, Icahn School of Medicine at Mount Sinai, Ehlers-Danlos Society, Ines Mandl Research Foundation, National Institutes of Health, European Research Council, 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 Biomedical Imaging and Bioengineering, National Institute of Dental and Craniofacial Research, National Center for Research Resources, National Center for Advancing Translational Sciences, Office of Extramural Research, National Institutes of Health
Awards: Molecular and cellular causes of mitral valve prolapse, G1250730630, G1359611882, G2205488568, G2218914908, G2934836127, G3289744341, G3841404249, G4923822789, G5192398045, G547628071, G6159548873, Training To Improve Cardiovascular Therapies, G6277984997, Targeting Mek/Erk Signaling in the Treatment of Mitral Valve Prolapse, Dzip1 and Mitral Valve Prolapse, SC COBRE for TranslationalResearch Improving MusculoskeletalHealth (SC-TRIMH), Integrating craniofacial morphology, oral function, temporomandibular biomechanics and mechanobiology to determine sex-specific TMJ pathophysiology in humans
OpenAlex ID: W4413184310