{
  "abstract": "Systemic sclerosis (SSc) is a rare, heterogeneous autoimmune disease characterized by immune dysregulation, vasculopathy and fibrosis. While typically sporadic, SSc can in a minority of cases show familial clustering. Whole exome sequencing (WES), performed on six families with two affected members each, identified a total of 253 genes with rare, disease co- segregating variants predicted to affect protein function. Of these, we prioritized PRKD2, one of only three genes identified in two families. PRKD2 encodes Protein kinase D2: an intracellular serine-threonine kinase that amplifies T cell receptor (TCR) signaling. Both familial SSc-associated PRKD2 missense variants increased kinase activation, exerting overlapping, activating effects on TCR signaling in heterozygous knock-in Jurkat cells. A pan- PRKD inhibitor suppressed T cell activation in peripheral blood mononuclear cells from both familial SSc cases and controls. The enrichment of PRKD2 rare variants in a sporadic SSc cohort provides further support for its relevance to SSc pathogenesis. Together, these findings identify PRKD2 rare variants as potential genetic contributors to SSc, and PRKD2-mediated TCR signaling as a candidate disease-relevant and potentially targetable pathway.",
  "abstract_shown": true,
  "affiliations": [
    "de Duve Institute, UCLouvain"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 20,
  "authors": [
    {
      "name": "P. Maus"
    },
    {
      "name": "G. Tilman"
    },
    {
      "name": "S. Boutry"
    },
    {
      "name": "A. Loriot"
    },
    {
      "name": "T. Conjard"
    },
    {
      "name": "J. Hatoum"
    },
    {
      "name": "A.-C. Dens"
    },
    {
      "name": "T. Du Four"
    },
    {
      "name": "D. Nolf"
    },
    {
      "name": "T. Hirsch"
    },
    {
      "name": "T. Gomard"
    },
    {
      "name": "R. Helaers"
    },
    {
      "name": "E. De Langhe"
    },
    {
      "name": "Y. Ishikawa"
    },
    {
      "name": "Y. Allanore"
    },
    {
      "name": "C. Terao"
    },
    {
      "name": "J. Fellay"
    },
    {
      "name": "M. Vanthuyne"
    },
    {
      "name": "V. Smith"
    },
    {
      "affs": [
        0
      ],
      "name": "N. Limaye"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2q1p9e6mfrgz1.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.20.26363195",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.20.26363195v1.full",
  "id": "2q1p9e6mfrgz1",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.20.26363195v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "rheumatology"
    ],
    [
      "openalex",
      "2734|Systemic Sclerosis and Related Diseases"
    ]
  ],
  "openalex": "W7214297664",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.20.26363195v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-20",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2q1p9e6mfrgz1.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:25Z",
      "native_id": "10.64898/2026.09.20.26363195",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.20.26363195v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:rheumatology",
      "subfield": "general"
    }
  ],
  "title": "Activating variants in PRKD2 in two families with Systemic sclerosis, and enrichment of rare variants in a sporadic series.",
  "title_text": "Activating variants in PRKD2 in two families with Systemic sclerosis, and enrichment of rare variants in a sporadic series.",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:25Z",
  "url": "https://research.draconitic.com/paper/2q1p9e6mfrgz1",
  "venue": "medRxiv",
  "versions": []
}