Activating variants in PRKD2 in two families with Systemic sclerosis, and enrichment of rare variants in a sporadic series
Year: 2026
Type: preprint
Study design: Observational Study
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.
Source: medRxiv
Authors: Pierre Maus, Gaëlle Tilman, Simon Boutry, Axelle Loriot, Thomas Conjard, Jinine Hatoum, Anne-Catherine Dens, Tessa Du Four, Delphine Nolf, Thibault Hirsch, Tiphanie Gomard, Raphaël Helaers, Ellen De Langhe, Yuki Ishikawa, Yannick Allanore, Chikashi Terao, Jacques Fellay, Marie Vanthuyne, Vanessa Smith, Nisha Limaye
Institutions: de Duve Institute, UCLouvain, SIB Swiss Institute of Bioinformatics, École Polytechnique Fédérale de Lausanne, Universitair Ziekenhuis Leuven, Ghent University Hospital, Ghent University, ERN ReCONNET, Fujita Health University, Université Paris Cité, Hôpital Cochin, Assistance Publique – Hôpitaux de Paris, Cliniques Universitaires Saint-Luc, CHU Dinant Godinne UCL Namur, VIB-UGent Center for Inflammation Research
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7214297664