title: DHPLC screening for mutations in progressive familial intrahepatic cholestasis patients.
abstract: Progressive familial intrahepatic cholestasis (PFIC) is a group of rare heterogeneous autosomal recessive disorders characterized by metabolic defects in biliary proteins involved in the formation and transfer of bile acids in the liver. The genotype-phenotype correlation is not always clear. Mutations in the ATP8B1, BSEP and MDR3 genes have been associated with PFIC1, PFIC2 and PFIC3, respectively. This study sought to characterize the molecular genetic basis for PFIC subtypes in Israel. It was conducted on 14 children with PFIC and their families; 10 with a PFIC1 or PFIC2 phenotype and 4 with a PFIC3 phenotype. Using denaturing high-performance liquid chromatography (DHPLC), five different mutations were identified in four affected families: three novel mutations in BSEP (G19R-g181c, S226L-c803t and G877R-g2755a), one novel mutation in MDR3 (IVS14+6 t/c) and one heterozygous mutation in ATP8B1 (R600W, in a family with the PFIC1/PFIC2 phenotype). The cause of PFIC was identified in 20% of the families tested. These findings indicate the probable involvement of additional genes in PFIC and the need for further studies to determine whether the abnormality lies on the RNA or protein level. A better understanding of the phenotype-genotype correlation in PFIC will lead to improved diagnoses and treatments.
authors.affiliation: Institute of Gastroenterology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
authors.forename: Rivka
authors.initials: R
authors.lastname: Shapiro
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.forename: Tal
authors.initials: T
authors.lastname: Yardeni
authors.forename: Sigal
authors.initials: S
authors.lastname: Korem
authors.forename: Korina
authors.initials: K
authors.lastname: Hartman
authors.forename: Raanan
authors.initials: R
authors.lastname: Shamir
authors.forename: Efrat
authors.initials: E
authors.lastname: Broide
authors.forename: Arie
authors.initials: A
authors.lastname: Levine
authors.forename: Yoram
authors.initials: Y
authors.lastname: Bujanover
authors.forename: Dani
authors.initials: D
authors.lastname: Bercovich
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; D001483:Base Sequence; D002675:Child, Preschool; D002780:Cholestasis, Intrahepatic / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007557:Israel; D008297:Male; D009154:Mutation; D010375:Pedigree; D012189:Retrospective Studies
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