Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3)

• Published in: European journal of human genetics : EJHG Vol. 15; no. 12; pp. 1230 - 1238
• Main Authors: DEGIORGIO, Dario, COLOMBO, Carla, SEIA, Manuela, PORCARO, Luigi, COSTANTINO, Lucy, ZAZZERON, Laura, BORDO, Domenico, COVIELLO, Domenico A
• Format: Journal Article
• Language: English
• Published: Avenel, NJ Nature Publishing 01-12-2007; Nature Publishing Group
• Subjects: ABC transporters; Alleles; Amino Acid Sequence; ATP Binding Cassette Transporter, Sub-Family B - chemistry; ATP Binding Cassette Transporter, Sub-Family B - genetics; ATP-Binding Cassette Transporters - chemistry; ATP-Binding Cassette Transporters - genetics; Bile; Biochemistry; Biological and medical sciences; Cholestasis; Cholestasis, Intrahepatic - genetics; Cirrhosis; Codon, Nonsense - genetics; Exons; Exons - genetics; Fundamental and applied biological sciences. Psychology; Gallbladder diseases; Gastroenterology. Liver. Pancreas. Abdomen; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Hereditary diseases; Homology; Humans; Lecithin; Liver diseases; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Mammals; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Mutagenesis, Insertional; Mutation; Mutation - genetics; Mutation, Missense - genetics; Other diseases. Semiology; Protein structure; Proteins; Sequence Alignment; Tertiary structure; Italy; Family study; Multicenter study; ABCB4; Biological marker; Hepatic disease; evolutionary marker; PFIC3; Biliary tract disease; allelic heterogeneity; Characterization; Progressive; Intrahepatic cholostasis; Molecular evolution; Heterogeneity; progressive familial intrahepatic cholestasis; Digestive diseases; Genetics; Mutation; MDR3
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/sj.ejhg.5201908

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 gamma-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.