Activating variants in PRKD2 in two families with Systemic sclerosis, and enrichment of rare variants in a sporadic series.
- 1de Duve Institute, UCLouvain
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.
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BibTeX
@misc{maus2026activating,
title = {{Activating variants in PRKD2 in two families with Systemic sclerosis, and enrichment of rare variants in a sporadic series.}},
author = {P. Maus and G. Tilman and S. Boutry and A. Loriot and T. Conjard and J. Hatoum and A.-C. Dens and T. Du Four and D. Nolf and T. Hirsch and T. Gomard and R. Helaers and E. De Langhe and Y. Ishikawa and Y. Allanore and C. Terao and J. Fellay and M. Vanthuyne and V. Smith and N. Limaye},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.20.26363195},
url = {https://www.medrxiv.org/content/10.64898/2026.09.20.26363195v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Activating variants in PRKD2 in two families with Systemic sclerosis, and enrichment of rare variants in a sporadic series.
AU - P. Maus
AU - G. Tilman
AU - S. Boutry
AU - A. Loriot
AU - T. Conjard
AU - J. Hatoum
AU - A.-C. Dens
AU - T. Du Four
AU - D. Nolf
AU - T. Hirsch
AU - T. Gomard
AU - R. Helaers
AU - E. De Langhe
AU - Y. Ishikawa
AU - Y. Allanore
AU - C. Terao
AU - J. Fellay
AU - M. Vanthuyne
AU - V. Smith
AU - N. Limaye
PY - 2026
DA - 2026/09/20
PB - medRxiv
DO - 10.64898/2026.09.20.26363195
UR - https://www.medrxiv.org/content/10.64898/2026.09.20.26363195v1
AB - 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.
ER -