Research ArticleLiver disease

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

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Science Translational Medicine  24 Feb 2021:
Vol. 13, Issue 582, eabb0036
DOI: 10.1126/scitranslmed.abb0036

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CD100 mutation primes PSC

Primary sclerosing cholangitis (PSC) is an inflammatory liver disease without effective treatments. Although genetic factors are thought to predispose to PSC, no causative mutation has yet been identified. Jiang et al. performed whole-exome sequencing on a family with autosomal dominant inheritance of PSC and identified a germline mutation in SEMA4D, encoding CD100. The mutation resulted in T cell functional defects, including impaired interferon-γ production. Mutation knock-in mice were more prone to develop severe cholangitis after toxin exposure, and adoptive transfer of wild-type T cells into knock-in mice resulted in less severe disease. This protective role of T cells in PSC might be exploited therapeutically.


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.

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