Journal article
KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome
iScience, v 28(9), 113343
19 Sep 2025
PMID: 40949095
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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•KLK15 identified as a novel disease gene in multiple families with hEDS•Knock-in mice have tendon, skin, and heart valve abnormalities similar to patients•Knock-in mice show altered immune signaling and extracellular matrix organization•Findings expand hEDS pathogenesis to proteolytic and immune dysregulation
Body system; Non-infectious disease; Biological process; Molecular genetics
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Details
- Title
- KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome
- Creators
- Cortney Gensemer - Medical University of South CarolinaTaylor Petrucci - Medical University of South CarolinaTyler Beck - Medical University of South CarolinaVictoria Daylor - Medical University of South CarolinaMolly Griggs - Medical University of South CarolinaCharlotte Griggs - Medical University of South CarolinaAmy Weintraub - Medical University of South CarolinaKathryn Byerly - Medical University of South CarolinaLilong Guo - Medical University of South CarolinaJordan Morningstar - Medical University of South CarolinaIsabelle Kornblau - Medical University of South CarolinaRachel Biggs - Medical University of South CarolinaKelsey Moore - Medical University of South CarolinaNatalie Koren - Medical University of South CarolinaChristina Hastings - Medical University of South CarolinaEmily Oberlies - Medical University of South CarolinaElla R. Zientara - Medical University of South CarolinaElsie Devey - Medical University of South CarolinaSarah Dooley - Medical University of South CarolinaKristina Stayer - Medical University of South CarolinaRoman Fenner - Medical University of South CarolinaKatherine Singleton - Medical University of South CarolinaSofia Luzbetak - Medical University of South CarolinaDeatra Bear - Medical University of South CarolinaRebecca Byrd - Medical University of South CarolinaJulianna Weninger - Medical University of South CarolinaErika Bistran - Medical University of South CarolinaGyda Beeson - Medical University of South CarolinaJoshua Kerns - Medical University of South CarolinaMadalyn Osterhaus - Medical University of South CarolinaEmily Fleck - Medical University of South CarolinaJillian Schnaudigel - Medical University of South CarolinaShaina Butler - Medical University of South CarolinaSydney Severance - Medical University of South CarolinaWiley Kendall - Medical University of South CarolinaJoe R. Delaney - Medical University of South CarolinaDaniel P. Judge - Medical University of South CarolinaPeng Chen - Clemson UniversityHai Yao - Clemson UniversityJan Guz - Medical University of South CarolinaAlexander Awgulewitsch - Medical University of South CarolinaSteven A. Kautz - Medical University of South CarolinaRupak Mukherjee - Ralph H. Johnson VA Medical CenterRobert Price - University of South CarolinaFraser Henderson - University of Maryland, BaltimoreSteven Shapiro - Medical University of South CarolinaClair A. Francomano - Indiana University School of MedicineJason C. Kovacic - Victor Chang Cardiac Research InstituteMark Lavallee - University of Pittsburgh Medical CenterAmy R. Kontorovich - Icahn School of Medicine at Mount SinaiTakiy-Eddine Berrandou - InsermSusan A. Slaugenhaupt - Center for Systems BiologyDavid Milan - Harvard UniversityAnne Maitland - Medical University of South CarolinaSunil Patel - Medical University of South CarolinaNabila Bouatia-Naji - InsermRussell A. Norris (Corresponding Author) - Medical University of South Carolina
- Publication Details
- iScience, v 28(9), 113343
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine
- Web of Science ID
- WOS:001565806800001
- Scopus ID
- 2-s2.0-105014629703
- Other Identifier
- 991022197418504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Immunology