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

Sci Transl Med. 2021 Feb 24;13(582):eabb0036. 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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics*
  • Cholangitis, Sclerosing* / genetics
  • Gene Knock-In Techniques
  • Germ Cells
  • Germ-Line Mutation
  • Interferon-gamma
  • Mice
  • Semaphorins / genetics*
  • T-Lymphocytes


  • Antigens, CD
  • CD100 antigen
  • Semaphorins
  • Interferon-gamma