A segregating PTK2B variant in a primary biliary cholangitis (PBC) family induces PBC-like autoimmune features in knock-in mice.

backgroundPrimary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease with an incompletely understood genetic basis. This study aimed to identify disease-causing genetic variants in a PBC family and to evaluate their functional relevance in vivo.

resultsA total of 27 family members were enrolled in the analysis, among whom three were affected. After filtering of the whole-exome sequencing results of the PBC family, 17 candidate variants were identified, among which a protein tyrosine kinase 2β (PTK2B) c.1679C > G variant exclusively co-segregated with PBC in affected family members and was absent in unaffected relatives, healthy controls, and public databases. Homozygous knock-in mice exhibited significantly elevated serum alkaline phosphatase (236 ± 55 vs. 142 ± 43 U/L, P = 0.01) and antimitochondrial antibody levels (3924 ± 769 vs. 1972 ± 632 U/mL, P = 0.001) compared with heterozygous mice, along with portal lymphocytic infiltration, intrahepatic bile duct proliferation, and liver fibrosis. Female homozygous knock-in mice showed increased hepatic infiltration of CD3

conclusionsThis study identifies a segregating PTK2B variant in a family with PBC and demonstrates that the corresponding knock-in mutation induces PBC-like autoimmune features in mice. These findings provide human genetic and in vivo evidence supporting PTK2B as a candidate susceptibility gene for PBC.