A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis.

Authors:
Xiaojun Jiang, Annika Bergquist, Britt-Sabina Löscher, Geetha Venkatesh, Jeff E Mold, Kristian Holm, Jon K Laerdahl, Sigrid S Skånland, Kimia T Maleki, Martin Cornillet, Kjetil Taskén, Andre Franke, Tom H Karlsen, Niklas K Björkström, Espen Melum
Year of publication:
2021
Volume:
13
Issue:
582
Issn:
1946-6234
Journal title abbreviated:
SCI TRANSL MED
Journal title long:
Science Science translational medicine
Impact factor:
17.992
Abstract:
Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease without clear etiology or effective treatment. Genetic factors contribute to PSC pathogenesis, but so far, no causative mutation has been found. We performed whole-exome sequencing in a family with autosomal dominant inheritance of PSC and identified a heterozygous germline missense mutation in <i>SEMA4D</i>, encoding a K849T variant of CD100. The mutation was located in an evolutionarily conserved, unstructured cytosolic region of CD100 affecting downstream signaling. It was found to alter the function of CD100-expressing cells with a bias toward the T cell compartment that caused increased proliferation and impaired interferon-γ (IFN-γ) production after stimulation. Homologous mutation knock-in mice developed similar IFN-γ impairment in T cells and were more prone to develop severe cholangitis when exposed to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Transfer of wild-type T cells to knock-in mice before and during DDC exposure attenuated cholangitis. Taken together, we identified an inherited mutation in the disordered cytosolic region of CD100 resulting in T cell functional defects. Our findings suggest a protective role for T cells in PSC that might be used therapeutically.