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

• Published in: Science translational medicine 2021-02, Vol.13 (582), p.eabb0036
• Main Authors: Jiang, Xiaojun, Bergquist, Annika, Löscher, Britt-Sabina, Venkatesh, Geetha, Mold, Jeff E, Holm, Kristian, Laerdahl, Jon K, Skånland, Sigrid S, Maleki, Kimia T, Cornillet, Martin, Taskén, Kjetil, Franke, Andre, Karlsen, Tom H, Björkström, Niklas K, Melum, Espen
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - genetics; Autosomal dominant inheritance; Cholangitis; Cholangitis, Sclerosing - genetics; Etiology; Gene Knock-In Techniques; Genetic factors; Germ Cells; Germ-Line Mutation; Heredity; Interferon-gamma; Liver diseases; Lymphocytes; Lymphocytes T; Medicin och hälsovetenskap; Mice; Missense mutation; Mutation; Semaphorins - genetics; T-Lymphocytes; γ-Interferon
• ISSN: 1946-6234; 1946-6242; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.abb0036

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 , 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.