Abstract
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal-recessive disorder due to mutations in the ATP-binding cassette, subfamily B, member 4 gene (ABCB4). ABCB4 is the liver-specific membrane transporter of phosphatidylcholine, a major and exclusive component of mammalian bile. The disease is characterized by early onset of cholestasis with high serum γ-glutamyltranspeptidase activity, which progresses into cirrhosis and liver failure before adulthood. Presently, about 20 distinct ABCB4 mutations associated to PFIC3 have been described. We report the molecular characterization of 68 PFIC3 index cases enrolled in a multicenter study, which represents the largest cohort of PFIC3 patients screened for ABCB4 mutations to date. We observed 31 mutated ABCB4 alleles in 18 index cases with 29 distinct mutations, 25 of which are novel. Despite the lack of structural information on the ABCB4 protein, the elucidation of the three-dimensional structure of bacterial homolog allows the three-dimensional model of ABCB4 to be built by homology modeling and the position of the mutated amino-acids in the protein tertiary structure to be located. In a significant fraction of the cases reported in this study, the mutation should result in substantial impairment of ABCB4 floppase activity. The results of this study provide evidence of the broad allelic heterogeneity of the disease, with causative mutations spread along 14 of the 27 coding exons, but with higher prevalence on exon 17 that, as recently shown for the closely related paralogous ABCB1 gene, could contain an evolutionary marker for mammalian ABCB4 genes in the seventh transmembrane segment.
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Acknowledgements
We thank the families of the patients for their collaboration. This study was supported in part by the Italian Ministry of University and Research (MIUR), PRIN contract number 2005068307; grant Regione Lombardia, DG Sanità n. 12298 (2004), DG Sanità n.19081 (2005) and by Eurogentest-Network of Excellence, contract n.o. FP6-512148-2004. We are grateful to the participants in the ‘Multicenter study of Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition’: Prof G Maggiore, Clinica Pediatrica Università di Pisa; Dr G Torre, Centro Trapianto di Fegato, Bergamo; Dr R Iorio, Clinica Pediatrica, Università di Napoli; Dr M Resti, Azienda Ospedaliera Meyer, Firenze; Dr M Calacoci, Clinica Pediatrica, Università di Ferrara; Dr E Castellano (U. O. Pediatria III) and MG Marazzi (U. O. Malattie Infettive), IRCCS G. Gaslini, Genova; Prof F Balli, Clinica Pediatrica, Università di Modena; Prof P Vajro, Dipartimento di Pediatria, Università di Napoli; Dr E Ferretti, ASL 1 Napoli est; Prof L Zancan, Clinica pediatrica, Università di Padova; Dr S Martelossi, Clinica Pediatrica, IRCCS Burlo Garofalo, Trieste; Dr F Oliveri, U.O. Gastroenterologia ed Epatologia, Ospedale S Chiara, Pisa. We are grateful to Dr. Giandomenico Russo for oligonucleotides sequences.
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Degiorgio, D., Colombo, C., Seia, M. et al. Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3). Eur J Hum Genet 15, 1230–1238 (2007). https://doi.org/10.1038/sj.ejhg.5201908
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DOI: https://doi.org/10.1038/sj.ejhg.5201908
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