title: Bile salt export pump deficiency disease: two novel, late onset, ABCB11 mutations identified by next generation sequencing.
abstract: Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive cholestatic diseases of childhood and represents the main indication for liver transplantation at this age; PFIC2 involves ABCB11 gene, that encodes the ATPdependent canalicular bile salt export pump (BSEP). Benign intrahepatic cholestasis (BRIC) identifies a group of diseases involving the same genes and characterized by intermittent attacks of cholestasis with no progression to liver cirrhosis. Diagnosis with standard sequencing techniques is expensive and available only at a few tertiary centers. We report the application of next generation sequencing (NGS) in the diagnosis of the familial intrahepatic cholestasis with a parallel sequencing of three causative genes. We identified the molecular defects in ABCB11 gene in two different probands who developed a severe cholestatic disease of unknown origin. In the first patient a compound heterozygosity for the novel frameshift mutation p.Ser1100GlnfsX38 and the missense variant p.Glu135Lys was detected. In the second patient, triggered by contraceptive therapy, we identified homozygosity for a novel missense variant p.Ala523Gly. In conclusion, these mutations seem to have a late onset and a less aggressive clinical impact, acting as an intermediate form between BRIC and PFIC.
authors: Department of Medical and Surgical Sciences, University of Bologna, Bologna.
authors: Giovanni
authors: G
authors: Vitale
authors: Department of Medical and Surgical Sciences, University of Bologna, Bologna.
authors: Martina
authors: M
authors: Pirillo
authors: Center for Applied Biomedical Research (CRBA), University of Bologna, Bologna.
authors: Vilma
authors: V
authors: Mantovani
authors: Center for Applied Biomedical Research (CRBA), University of Bologna, Bologna.
authors: Elena
authors: E
authors: Marasco
authors: Center for Applied Biomedical Research (CRBA), University of Bologna, Bologna.
authors: Adelia
authors: A
authors: Aquilano
authors: Department of Medical and Surgical Sciences, University of Bologna, Bologna.
authors: Nesrine
authors: N
authors: Gamal
authors: Department of Pathology, Bambino Gesù Children's Hospital, University of Rome, Rome.
authors: Paola
authors: P
authors: Francalanci
authors: Department of Medical and Surgical Sciences, University of Bologna, Bologna.
authors: Fabio
authors: F
authors: Conti
authors: Department of Medical and Surgical Sciences, University of Bologna, Bologna.
authors: Pietro
authors: P
authors: Andreone
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics*; D001647:Bile Acids and Salts / Q000378:metabolism*; D002780:Cholestasis, Intrahepatic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts