P0035 PP BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS IS CAUSED BY MUTATIONS IN ABCB11 AS WELL AS ATP8B1

Abstract

Introduction: Benign Recurrent Intrahepatic Cholestasis (BRIC) is an autosomal recessive liver disease, characterized by intermittent attacks of cholestasis without anatomical obstruction. Patients characteristically have a normal serum gamma-glutamyl transpeptidase (GGT) activity and will not develop permanent liver damage. In contrast, patients with Progressive Familial In-trahepatic Cholestasis (PFIC), also characterized by normal GGT activity, will invariably develop liver cirrhosis and ultimately liver failure. ATP8B1 (FIC1) is mutated in PFIC subtype 1 (PFIC1) whereas ABCB11 (BSEP) is mutated in PFIC subtype 2 (PFIC2). In BRIC patients currently only mutations in ATP8B1 have been described. Methods: In a previous study we could not identify mutations in ATP8B1 in 23 out of 44 patients with BRIC. Because of the resemblance in clinical phenotypes between PFIC1 and PFIC2, we hypothesized that these patients might harbour mutations in ABCB11. We therefore sequenced all 27 coding ABCB11 exons, including splice site junctions, in the 23 BRIC patients without ATP8B1 mutations. Results: We detected mutations in ABCB11 in 10 out of the 23 BRIC patients. Our analysis revealed one homozygous mis-sense mutation previously described in PFIC2 patients, 11 novel missense mutations and one novel splice site mutation in ABCB11. None of these mutations were found in 494 control chromosomes. Seven missense mutations are positioned in proximity of the different transmembrane domains, probably causing misfolding of BSEP. Three missense mutations are located in the highly conserved domain between the linkerpeptide and the walker B motifs. Pancreatitis is sometimes observed in BRIC caused by mutations in ATP8B1, but was not seen in 10 ABCB11-affected BRIC patients. Apart from the lack of pancreatitic involvement no consistent clinical differences were detected between BRIC patients with mutations in ATP8B1 and ABCB11. Finally, in 13 BRIC patients no mutations have been found in either ATP8B1 or ABCB11, suggesting that there may be yet another locus for autosomal recessive BRIC. Conclusion: We have established that mutations in ABCB11 are associated with BRIC. BSEP deficiency therefore has a broad clinical spectrum, similar as FIC1 deficiency.