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

Primary 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.

A 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⁺ T cells (50.8% ± 1.7% vs. 38.9% ± 3.2%, P = 0.005), CD8⁺ T cells (14.3% ± 2.8% vs. 7.5% ± 1.3%, P = 0.005), CD19⁺ B cells (44.7% ± 1.7% vs. 32.6% ± 2.2%, P = 0.002), and CCR2⁺ cells (31.7% ± 6.2% vs. 20.4% ± 2.2%, P = 0.03), accompanied by reduced CCR2⁺ cells in peripheral blood (4.8% ± 6.5% vs. 33.8% ± 12.8%, P = 0.001) and elevated serum MCP-1 levels (2209 ± 412 vs. 1187 ± 89 pg/mL, P < 0.0001) than wildtype mice.

This 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.