Evidence map›Paper›PMID 40949095›Full record

ArticleiScience2025

KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome.

Cortney Gensemer, Taylor Petrucci, Tyler Beck, Victoria Daylor, Molly Griggs, Charlotte Griggs, Amy Weintraub, Kathryn Byerly, Lilong Guo, Jordan Morningstar and 47 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in iScience, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed.

  1. Transcutaneous auricular vagus nerve stimulation improves dysautonomia in patients with hypermobile Ehlers-Danlos syndrome.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026
    Article
  2. AnBiomedicines · 2026
    Article
  3. Article
  4. Drug Discovery Strategies for Kallikrein-Related Peptidases.International journal of molecular sciences · 2025
    Review
  5. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

57 authors.

Cortney GensemerDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Taylor PetrucciDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Tyler BeckDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Victoria DaylorDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Molly GriggsDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Charlotte GriggsDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Amy WeintraubDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Kathryn ByerlyDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Lilong GuoDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Jordan MorningstarDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Isabelle KornblauDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Rachel BiggsDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Kelsey MooreDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Natalie KorenDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Christina HastingsDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Emily OberliesDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Ella R ZientaraDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Elsie DeveyDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Sarah DooleyDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Kristina StayerDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Roman FennerDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Katherine SingletonDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Sofia LuzbetakDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Deatra BearDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Rebecca ByrdDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Julianna WeningerDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Erika BistranDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Gyda BeesonDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Joshua KernsDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Madalyn OsterhausDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Emily FleckDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Jillian SchnaudigelDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Shaina ButlerDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Sydney SeveranceDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Wiley KendallDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Joe R DelaneyDepartment of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29407, USA.
Daniel P JudgeDivision of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29407, USA.
Peng ChenClemson-MUSC Joint Bioengineering Program, Department of Bioengineering, Clemson University, Clemson, SC 29634, USA.
Hai YaoClemson-MUSC Joint Bioengineering Program, Department of Bioengineering, Clemson University, Clemson, SC 29634, USA.
Jan GuzDepartment of Regenerative Medicine and Cell Biology, Transgenic and Gene Function Core, Medical University of South Carolina, Charleston, SC 29407, USA.
Alexander AwgulewitschDepartment of Regenerative Medicine and Cell Biology, Transgenic and Gene Function Core, Medical University of South Carolina, Charleston, SC 29407, USA.
Steven A KautzDepartment of Health Sciences and Research, Medical University of South Carolina, Charleston, SC 29407, USA.
Rupak MukherjeeRalph H. Johnson VA Medical Center, Charleston, SC 29407, USA.
Robert PriceDepartment of Cell Biology and Anatomy, University of South Carolina, School of Medicine, Columbia, SC 29208, USA.
Fraser HendersonDivision of Neurosurgery, University of Maryland Capitol Regional Medical Center, Largo, MD 20774, USA.
Steven ShapiroCollege of Dental Medicine, Medical University of South Carolina, Charleston, SC 29407, USA.
Clair A FrancomanoDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Jason C KovacicCardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Mark LavalleeDepartment of Sports Medicine, University of Pittsburgh Medical Center, Harrisburg, PA 17109, USA.
Amy R KontorovichCardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Takiy-Eddine BerrandouUniversité de Paris, PARCC, INSERM, 75015 Paris, France.
Susan A SlaugenhauptDepartment of Neurology, Center for Genomic Medicine, Massachusetts General Research Institute, Harvard Medical School, Boston, MA 02114, USA.
David MilanCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Anne MaitlandDivision of Rheumatology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29407, USA.
Sunil PatelDepartment of Neurosurgery, Medical University of South Carolina, Charleston, SC 29407, USA.
Nabila Bouatia-NajiUniversité de Paris, PARCC, INSERM, 75015 Paris, France.
Russell A NorrisDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, USA.

Funding

Tissue Structural and Neural Remodeling in Human Sacroiliac JointP20GM121342 · NIGMS · CLEMSON UNIVERSITY · PI Hai Yao · 2018 to 2026
$24.7M
The Center for Label-free Imagingand Multiscale Biophotonics (CLIMB)P41EB031772 · NIBIB · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · PI Stephen A Boppart · 2022 to 2026
$7.6M
Copy Number Alterations in Low Mutation CancerR00CA207729 · NCI · MEDICAL UNIVERSITY OF SOUTH CAROLINA · PI DELANEY, JOE R · 2019 to 2021
$730k
Genetic and Molecular Mechanisms of hypermobile Ehlers Danlos SyndromeF32AI181339 · NIAID · MEDICAL UNIVERSITY OF SOUTH CAROLINA · PI Cortney Anne Gensemer · 2024 to 2026
$170k
NCI NIH HHS R00 CA207729NIAID NIH HHS F32 AI181339NIBIB NIH HHS P41 EB031772NIGMS NIH HHS P20 GM121342
6 · The paper itself

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.

Indexed as

Biological processBody systemMolecular geneticsNon-infectious disease

Identifiers

PMID40949095
PMCPMC12424230

What OpenQuestion holds

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LicenceCC BY-NC-ND
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.