A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis
- 24 February 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 13 (582)
- https://doi.org/10.1126/scitranslmed.abb0036
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 SEMA4D, 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.Funding Information
- Swedish Foundation for Strategic Research
- Karolinska Institutet
- Helse Sør-Øst RHF
- Novo Nordisk Foundation Center for Basic Metabolic Research
- Swedish Research Council
- Swedish Cancer Society
- Knut and Alice Wallenberg Foundation
- Swedish Society for Medical Research
- The Norwegian PSC Centre
- Cancer Research Foundations of Radiumhemmet
- Region Stockholm
- the K.G. Jebsen Inflammation Research Centre
- the Center for Innovative Medicine
- the DFG Clinical Research Unit (306 ‘Primary Sclerosing Cholangitis’)
- the DFG Excellence Cluster ‘Precision Medicine in Chronic Inflammation’
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