title: ABCB4 sequence variations in young adults with cholesterol gallstone disease.
abstract: OBJECTIVE
  Mutations in the gene encoding the ABCB4 [adenosine triphosphate (ATP)-binding cassette, sub-family B (MDR/TAP), member 4] transporter lower phosphatidylcholine output into bile and contribute to cholesterol gallstone formation by decreasing the solubility of cholesterol in bile. Mutations in ABCB4 have been identified in patients with low phospholipid-associated cholelithiasis. The aim of the present study was to determine the types and frequencies of ABCB4 mutations in cholecystectomized patients aged <40 years.
  
  
  METHODS
  Hundred and four patients (mean age 30.6 years, range 12-39) were included in the study and the ABCB4 gene was sequenced. The frequency of missense mutations found in the patient material was measured in 95 healthy controls. The potential functional implications of the ABCB4 missense variations were assessed by computerized analysis (BLOSUM62 and Grantham substitution matrices, polymorphism phenotyping and sorting intolerant from tolerant).
  
  
  RESULTS
  One patient was heterozygous for a frameshift mutation (c.1399_1400ins10/p.Y467F fsX25). Another patient was heterozygous for a nonsense mutation (c.3136C>T/p.R1046X). These two mutations are considered detrimental to ABCB4 protein function. In addition, six missense mutations were found in the ABCB4 gene, and three of these were only present in patients.
  
  
  CONCLUSIONS
  In our study, <2% of young gallstone patients were found to be heterozygous for detrimental ABCB4 mutations. The functional implication of several missense mutations remains to be clarified. Thus, mutations in the ABCB4 gene are a rare cause of gallstone disease.
authors.affiliation: Institute for Experimental Medical Research, Ullevaal University Hospital, Oslo, Norway. esten.nakken@medisin.uio.no
authors.forename: Karl Esten
authors.initials: KE
authors.lastname: Nakken
authors.forename: Knut Jørgen
authors.initials: KJ
authors.lastname: Labori
authors.forename: Olaug K
authors.initials: OK
authors.lastname: Rødningen
authors.forename: Sigve
authors.initials: S
authors.lastname: Nakken
authors.forename: Knut E
authors.initials: KE
authors.lastname: Berge
authors.forename: Kristin
authors.initials: K
authors.lastname: Eiklid
authors.forename: Morten G
authors.initials: MG
authors.lastname: Raeder
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002784:Cholesterol / Q000737:chemistry; D005260:Female; D042882:Gallstones / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009664:Norway
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D002784:Cholesterol; C095122:multidrug resistance protein 3