Peer-reviewedCC BY-NC-ND 4.0iScience
KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome
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. Wholeexome 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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BibTeX
@article{gensemer2026klk15,
title = {{KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome}},
author = {Cortney Gensemer and Taylor Petrucci and Tyler Beck and Victoria Daylor and Molly Griggs and Charlotte Griggs and Amy Weintraub and Kathryn Byerly and Lilong Guo and Jordan Morningstar and Isabelle Kornblau and Rachel Biggs and Kelsey Moore and Natalie Koren and Christina Hastings and Emily Oberlies and Ella R Zientara and Elsie Devey and Sarah Dooley and Kristina Stayer and Roman Fenner and Katherine Singleton and Sofia Luzbetak and Deatra Bear and Rebecca Byrd and Julianna Weninger and Erika Bistran and Gyda Beeson and Joshua Kerns and Madalyn Osterhaus and Emily Fleck and Jillian Schnaudigel and Shaina Butler and Sydney Severance and Wiley Kendall and Joe R Delaney and Daniel P Judge and Peng Chen and Hai Yao and Jan Guz and Alexander Awgulewitsch and Steven A Kautz and Rupak Mukherjee and Robert Price and Fraser Henderson and Steven Shapiro and Clair A Francomano and Jason C Kovacic and Mark Lavallee and Amy R Kontorovich and Takiy-Eddine Berrandou and Susan A Slaugenhaupt and David Milan and Anne Maitland and Sunil Patel and Nabila Bouatia-Naji and Russell A Norris},
journal = {iScience},
year = {2026},
month = oct,
doi = {10.1016/j.isci.2025.113343},
url = {https://hal.science/hal-05794464v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome
AU - Cortney Gensemer
AU - Taylor Petrucci
AU - Tyler Beck
AU - Victoria Daylor
AU - Molly Griggs
AU - Charlotte Griggs
AU - Amy Weintraub
AU - Kathryn Byerly
AU - Lilong Guo
AU - Jordan Morningstar
AU - Isabelle Kornblau
AU - Rachel Biggs
AU - Kelsey Moore
AU - Natalie Koren
AU - Christina Hastings
AU - Emily Oberlies
AU - Ella R Zientara
AU - Elsie Devey
AU - Sarah Dooley
AU - Kristina Stayer
AU - Roman Fenner
AU - Katherine Singleton
AU - Sofia Luzbetak
AU - Deatra Bear
AU - Rebecca Byrd
AU - Julianna Weninger
AU - Erika Bistran
AU - Gyda Beeson
AU - Joshua Kerns
AU - Madalyn Osterhaus
AU - Emily Fleck
AU - Jillian Schnaudigel
AU - Shaina Butler
AU - Sydney Severance
AU - Wiley Kendall
AU - Joe R Delaney
AU - Daniel P Judge
AU - Peng Chen
AU - Hai Yao
AU - Jan Guz
AU - Alexander Awgulewitsch
AU - Steven A Kautz
AU - Rupak Mukherjee
AU - Robert Price
AU - Fraser Henderson
AU - Steven Shapiro
AU - Clair A Francomano
AU - Jason C Kovacic
AU - Mark Lavallee
AU - Amy R Kontorovich
AU - Takiy-Eddine Berrandou
AU - Susan A Slaugenhaupt
AU - David Milan
AU - Anne Maitland
AU - Sunil Patel
AU - Nabila Bouatia-Naji
AU - Russell A Norris
PY - 2026
DA - 2026/10/12
JO - iScience
DO - 10.1016/j.isci.2025.113343
UR - https://hal.science/hal-05794464v1
AB - 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. Wholeexome 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.
SN - 2589-0042
ER -