| First Author | Jiang X | Year | 2021 |
| Journal | Sci Transl Med | Volume | 13 |
| Issue | 582 | PubMed ID | 33627483 |
| Mgi Jnum | J:302974 | Mgi Id | MGI:6508655 |
| Doi | 10.1126/scitranslmed.abb0036 | Citation | Jiang X, et al. (2021) A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis. Sci Transl Med 13(582) |
| abstractText | 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-gamma (IFN-gamma) production after stimulation. Homologous mutation knock-in mice developed similar IFN-gamma 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. |
