Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11.
OBJECTIVE
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 1 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.
van Mil
Saskia W C
SW
Department of Metabolic and Endocrine Diseases, University Medical Center, Utrecht, The Netherlands.
van der Woerd
Wendy L
WL
van der Brugge
Gerda
G
Sturm
Ekkehard
E
Jansen
Peter L M
PL
Bull
Laura N
LN
van den Berg
Inge E T
IE
Berger
Ruud
R
Houwen
Roderick H J
RH
Klomp
Leo W J
LW
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D002780:Cholestasis, Intrahepatic / Q000145:classification / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D012008:Recurrence
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters