{
  "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.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 57,
  "authors": [
    {
      "name": "Cortney Gensemer"
    },
    {
      "name": "Taylor Petrucci"
    },
    {
      "name": "Tyler Beck"
    },
    {
      "name": "Victoria Daylor"
    },
    {
      "name": "Molly Griggs"
    },
    {
      "name": "Charlotte Griggs"
    },
    {
      "name": "Amy Weintraub"
    },
    {
      "name": "Kathryn Byerly"
    },
    {
      "name": "Lilong Guo"
    },
    {
      "name": "Jordan Morningstar"
    },
    {
      "name": "Isabelle Kornblau"
    },
    {
      "name": "Rachel Biggs"
    },
    {
      "name": "Kelsey Moore"
    },
    {
      "name": "Natalie Koren"
    },
    {
      "name": "Christina Hastings"
    },
    {
      "name": "Emily Oberlies"
    },
    {
      "name": "Ella R Zientara"
    },
    {
      "name": "Elsie Devey"
    },
    {
      "name": "Sarah Dooley"
    },
    {
      "name": "Kristina Stayer"
    },
    {
      "name": "Roman Fenner"
    },
    {
      "name": "Katherine Singleton"
    },
    {
      "name": "Sofia Luzbetak"
    },
    {
      "name": "Deatra Bear"
    },
    {
      "name": "Rebecca Byrd"
    },
    {
      "name": "Julianna Weninger"
    },
    {
      "name": "Erika Bistran"
    },
    {
      "name": "Gyda Beeson"
    },
    {
      "name": "Joshua Kerns"
    },
    {
      "name": "Madalyn Osterhaus"
    },
    {
      "name": "Emily Fleck"
    },
    {
      "name": "Jillian Schnaudigel"
    },
    {
      "name": "Shaina Butler"
    },
    {
      "name": "Sydney Severance"
    },
    {
      "name": "Wiley Kendall"
    },
    {
      "name": "Joe R Delaney"
    },
    {
      "name": "Daniel P Judge"
    },
    {
      "name": "Peng Chen"
    },
    {
      "name": "Hai Yao"
    },
    {
      "name": "Jan Guz"
    },
    {
      "name": "Alexander Awgulewitsch"
    },
    {
      "name": "Steven A Kautz"
    },
    {
      "name": "Rupak Mukherjee"
    },
    {
      "name": "Robert Price"
    },
    {
      "name": "Fraser Henderson"
    },
    {
      "name": "Steven Shapiro"
    },
    {
      "name": "Clair A Francomano"
    },
    {
      "name": "Jason C Kovacic"
    },
    {
      "name": "Mark Lavallee"
    },
    {
      "name": "Amy R Kontorovich"
    },
    {
      "name": "Takiy-Eddine Berrandou"
    },
    {
      "name": "Susan A Slaugenhaupt"
    },
    {
      "name": "David Milan"
    },
    {
      "name": "Anne Maitland"
    },
    {
      "name": "Sunil Patel"
    },
    {
      "name": "Nabila Bouatia-Naji"
    },
    {
      "name": "Russell A Norris"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3gxtrttaan6a7.bib",
  "cited_by": 12,
  "doi": "10.1016/j.isci.2025.113343",
  "fulltext_url": null,
  "id": "3gxtrttaan6a7",
  "issns": [
    "2589-0042"
  ],
  "landing_url": "https://hal.science/hal-05794464v1",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.sdv"
    ],
    [
      "openalex",
      "1311|Connective tissue disorders research"
    ]
  ],
  "openalex": "W4413184310",
  "pdf_url": "https://hal.science/hal-05794464/document",
  "pmcid": null,
  "pmid": "40949095",
  "published": "2026-10-12",
  "publisher": "Cell Press, Elsevier [2018-....]",
  "ris": "https://research.draconitic.com/paper/3gxtrttaan6a7.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:54Z",
      "native_id": "hal-05794464",
      "source": "hal",
      "url": "https://hal.science/hal-05794464v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Connective tissue disorders research",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome",
  "title_text": "KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:54Z",
  "url": "https://research.draconitic.com/paper/3gxtrttaan6a7",
  "venue": "iScience",
  "versions": []
}