Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11

Background & Aims: Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are hereditary liver disorders; PFIC is characterized by severe progressive liver disease whereas BRIC patients have intermittent attacks of cholestasis without permanent liver damage. Mutations in ATP8B1 are present in PFIC type I and in a subset of BRIC patients. We hypothesized that a genetically distinct form of BRIC is associated with mutations in ABCB11. This gene encodes the bile salt export pump (BSEP) and is mutated in PFIC type 2. Methods: Patients from 20 families were included; all had a normal ATP8B1 sequence. Sequencing of all 27 coding exons including the splice junctions of ABCB11 revealed 8 distinct mutations in 11 patients from 8 different families: one homozygous missense mutation (E297G) previously described in PFIC2 patients, 6 novel missense mutations, and one putative splice site mutation. Results: In 12 families, no mutations in ATB8B1 or ABCB11 were detected. Pancreatitis is a known extrahepatic symptom in BRIC caused by ATP8B1 mutations, but was not present in BRIC patients with mutations in ABCB11. In contrast, cholelithiasis was observed in 7 of 11 BRIC patients with mutations in ABCB11, but has not been described in ATP8B1-affected BRIC patients. Conclusions: Mutations in ABCB11 are associated with BRIC, and consistent with the genetic classification of PFIC into 2 subtypes, we propose that this disorder be named BRIC type 2.