title: ABCB4 mutations underlie hormonal cholestasis but not pediatric idiopathic gallstones.
abstract: OBJECTIVE
  To investigate the contribution of ABCB4 mutations to pediatric idiopathic gallstone disease and the potential of hormonal contraceptives to prompt clinical manifestations of multidrug resistance protein 3 deficiency.
  
  
  METHODS
  Mutational analysis of ABCB4, screening for copy number variations by multiplex ligation-dependent probe amplification, genotyping for low expression allele c.1331T>C of ABCB11 and genotyping for variation c.55G>C in ABCG8 previously associated with cholesterol gallstones in adults was performed in 35 pediatric subjects with idiopathic gallstones who fulfilled the clinical criteria for low phospholipid-associated cholelithiasis syndrome (LPAC, OMIM #600803) and in 5 young females with suspected LPAC and their families (5 probands, 15 additional family members). The probands came to medical attention for contraceptive-associated intrahepatic cholestasis.
  
  
  RESULTS
  A possibly pathogenic variant of ABCB4 was found only in one of the 35 pediatric subjects with idiopathic cholesterol gallstones whereas 15 members of the studied 5 LPAC kindreds were confirmed and another one was highly suspected to carry predictably pathogenic mutations in ABCB4. Among these 16, however, none developed gallstones in childhood. In 5 index patients, all young females carrying at least one pathogenic mutation in one allele of ABCB4, manifestation of LPAC as intrahepatic cholestasis with elevated serum activity of gamma-glutamyltransferase was induced by hormonal contraceptives. Variants ABCB11 c.1331T>C and ABCG8 c.55G>C were not significantly overrepresented in the 35 examined patients with suspect LPAC.
  
  
  CONCLUSIONS
  Clinical criteria for LPAC syndrome caused by mutations in ABCB4 cannot be applied to pediatric patients with idiopathic gallstones. Sexual immaturity even prevents manifestation of LPAC.
authors.affiliation: Milan Jirsa, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Jirsa
authors.affiliation: Milan Jirsa, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Bronský
authors.affiliation: Milan Jirsa, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Dvořáková
authors.affiliation: Milan Jirsa, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Šperl
authors.affiliation: Milan Jirsa, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic.
authors.forename: Vít
authors.initials: V
authors.lastname: Šmajstrla
authors.affiliation: Milan Jirsa, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Horák
authors.affiliation: Milan Jirsa, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Nevoral
authors.affiliation: Milan Jirsa, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Hřebíček
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency* / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D002780:Cholestasis, Intrahepatic / Q000235:genetics*; D003278:Contraceptives, Oral, Hormonal / Q000009:adverse effects*; D004252:DNA Mutational Analysis; D005260:Female; D042882:Gallstones / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010743:Phospholipids / Q000378:metabolism; D055815:Young Adult
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D003278:Contraceptives, Oral, Hormonal; D010743:Phospholipids; C095122:multidrug resistance protein 3
keywords: Gallbladder disease 1; Idiopathic cholelithiasis; Intrahepatic cholestasis; Low phospholipid-associated cholelithiasis; Oral contraceptives