Gastroenterology

Gastroenterology

Volume 127, Issue 2, August 2004, Pages 379-384
Gastroenterology

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

https://doi.org/10.1053/j.gastro.2004.04.065Get rights and content

Abstract

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 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.

Section snippets

Patients

All studies were conducted under approved protocols in accordance with the guidelines of the children’s study committee of the University Medical Center Utrecht and referring centers. All BRIC patients had been diagnosed previously on the basis of clinical symptoms in combination with routine laboratory investigations. Inclusion criteria for this study were normal γ-glutamyl transpeptidase activity in serum and no obstruction of extrahepatic bile ducts. Patients were included only when at least

BSEP mutation analysis in BRIC patients

We screened all coding exons including intron-exon boundaries of ABCB11 for mutations in patients from 20 different BRIC families in whom ATP8B1 mutations had been excluded. Apparent homozygous ABCB11 mutations were detected in 7 patients from 5 families, and 3 patients from 2 families were compound heterozygous for ABCB11 mutations. In 1 patient (family 32) we detected only one heterozygous mutation. In total, 8 distinct mutations in ABCB11 were detected in 11 patients from 8 different

Discussion

We present a subtype of BRIC caused by mutations in ABCB11, the gene encoding the hepatocellular bile salt export pump (BSEP). This description of mutations in a gene other than ATP8B1 causing autosomal recessive BRIC, is consistent with previous preliminary findings.16 Autosomal-dominant BRIC also was reported, but the causative gene mutation has not been elucidated.17 To differentiate between the 2 distinct recessive forms of BRIC, we propose to denote BRIC caused by mutations in ATP8B1 as

Acknowledgements

The authors thank the participating families and referring physicians, and Frank Lammert for helpful discussions.

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    Supported by grant WS98-12 from the Dutch Digestive Disease Foundation (to L.W.J.K.), grant 2002B17 from the Dutch Heart Foundation (to E.S.), grant 902-23-191 from the Dutch Organization for Scientific Research (to P.L.M.J.), and R01 grant DK50697 from the National Institutes of Health (to L.N.B.).

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    The current address for P.L.M.J. is Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands.

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