title: Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy.
abstract: Intrahepatic cholestasis of pregnancy (ICP) is defined as pruritus and elevated bile acid serum concentrations in late pregnancy. Splicing mutations have been described in the multidrug resistance p-glycoprotein 3 (MDR3, ABCB4) gene in up to 20% of ICP women. Pedigrees studied were not large enough for linkage analysis. Ninety-seven family members of a woman with proven ICP were asked about pruritus in earlier pregnancies, birth complications and symptomatic gallstone disease. The familial cholestasis type 1 (FIC1, ATP8B1) gene, bile salt export pump (BSEP, ABCB11) and MDR3 gene were analyzed in 55 relatives. We identified a dominant mode of inheritance with female restricted expression and a new intronic MDR3 mutation c.3486+5G>A resulting in a 54 bp (3465-3518) inframe deletion via cryptic splicing site activation. Linkage analysis of the ICP trait versus this intragenic MDR3 variant yielded a LOD score of 2.48. A Bayesian analysis involving MDR3, BSEP, FIC1 and an unknown locus gave a posterior probability of >0.9966 in favor of MDR3 as causative ICP locus. During the episode of ICP the median gamma-glutamyl transpeptidase (gamma-GT) activity was 10 U/l (95% CI, 6.9 to 14.7 U/l) in the index woman. Four stillbirths were reported in seven heterozygous women (22 pregnancies) and none in five women (14 pregnancies) without MDR3 mutation. Symptomatic gallstone disease was more prevalent in heterozygous relatives (7/21) than in relatives without the mutation (1/34), (P = 0.00341).
  
  
  CONCLUSIONS
  This study demonstrates that splicing mutations in the MDR3 gene can cause ICP with normal gamma-GT and may be associated with stillbirths and gallstone disease.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schneider
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Paus
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meier
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wienker
authors.forename: Thomas
authors.initials: T
authors.lastname: Lang
authors.forename: Patricia
authors.initials: P
authors.lastname: van de Vondel
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Christoph
authors.initials: C
authors.lastname: Reichel
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002780:Cholestasis, Intrahepatic / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics*; D050497:Stillbirth / Q000235:genetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D004247:DNA; C095122:multidrug resistance protein 3