title: Genetics and Molecular Modeling of New Mutations of Familial Intrahepatic Cholestasis in a Single Italian Center.
abstract: Familial intrahepatic cholestases (FICs) are a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. Three distinct forms are described: FIC1 and FIC2, associated with low/normal GGT level in serum, which are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and defects in ABCB11 encoding bile salt export pump protein, respectively; FIC3, linked to high GGT level, involves impaired biliary phospholipid secretion due to defects in ABCB4, encoding multidrug resistance 3 protein. Different mutations in these genes may cause either a progressive familial intrahepatic cholestasis (PFIC) or a benign recurrent intrahepatic cholestasis (BRIC). For the purposes of the present study we genotyped 27 children with intrahepatic cholestasis, diagnosed on either a clinical or histological basis. Two BRIC, 23 PFIC and 2 BRIC/PFIC were identified. Thirty-four different mutations were found of which 11 were novel. One was a 2Mb deletion (5'UTR- exon 18) in ATP8B1. In another case microsatellite analysis of chromosome 2, including ABCB11, showed uniparental disomy. Two cases were compound heterozygous for BRIC/PFIC2 mutations. Our results highlight the importance of the pathogenic role of novel mutations in the three genes and unusual modes of their transmission.
authors.affiliation: Dept. Pathology and Molecular Histopathology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Giovannoni
authors.affiliation: Dept. Pathology and Molecular Histopathology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Callea
authors.affiliation: Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Bellacchio
authors.affiliation: Dept. Hepatology, Gastroenterology and Nutrition Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Torre
authors.affiliation: Dept. Pediatric Surgery and Transplantation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Jean
authors.initials: J
authors.lastname: De Ville De Goyet
authors.affiliation: Dept. Pathology and Molecular Histopathology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Francalanci
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D000293:Adolescent; D002675:Child, Preschool; D002780:Cholestasis, Intrahepatic / Q000235:genetics* / Q000473:pathology; D005838:Genotype; D006801:Humans; D007223:Infant; D007558:Italy; D008099:Liver / Q000473:pathology; D009154:Mutation / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017384:Sequence Deletion / Q000235:genetics; D024182:Uniparental Disomy / Q000235:genetics; D055815:Young Adult
chemical_list: C093491:ABCB11 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C095122:multidrug resistance protein 3; D000251:Adenosine Triphosphatases; C111067:ATP8B1 protein, human