title: First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis.
abstract: The wide clinical spectrum of the ABCB4 gene (ATP-binding cassette subfamily B member 4) deficiency syndromes in humans includes low phospholipid-associated cholelithiasis (LPAC), intrahepatic cholestasis of pregnancy (ICP), oral contraceptives-induced cholestasis (CIC), and progressive familial intrahepatic cholestasis type 3 (PFIC3). No ABCB4 mutations are found in a significant proportion of patients with these syndromes. In the present study, 102 unrelated adult patients with LPAC (43 patients) or CIC/ICP (59 patients) were screened for ABCB4 mutations using DNA sequencing. Heterozygous ABCB4 point or short insertion/deletion mutations were found in 37% (16/43) of the LPAC patients and in 27% (16/59) of the ICP/CIC patients. High-resolution gene dosage methodologies were used in the 70 negative patients. Here, we describe for the first time ABCB4 partial or complete heterozygous deletions in 7% (3/43) of the LPAC patients, and in 2% (1/59) of the ICP/CIC patients. Our observations urge to systematically test patients with LPAC, ICP/CIC, and also children with PFIC3 for the presence of ABCB4 deletions using molecular tools allowing detection of gross rearrangements. In clinical practice, a comprehensive ABCB4 alteration-screening algorithm will permit the use of ABCB4 genotyping to confirm the diagnosis of LPAC or ICP/CIC, and allow familial testing. An early diagnosis of these biliary diseases may be beneficial because of the preventive effect of ursodeoxycholic acid on biliary complications. Further comparative studies of patients with well-characterized genotypes (including deletions) and phenotypes will help determine whether ABCB4 mutation types influence clinical outcomes.
authors: Service de Biochimie et de Génétique Moléculaire, Hôpital Beaujon, Clichy, France. eric.pasmant@gmail.com
authors: Eric
authors: E
authors: Pasmant
authors: Philippe
authors: P
authors: Goussard
authors: Laetitia
authors: L
authors: Baranes
authors: Ingrid
authors: I
authors: Laurendeau
authors: Samuel
authors: S
authors: Quentin
authors: Philippe
authors: P
authors: Ponsot
authors: Yann
authors: Y
authors: Consigny
authors: Olivier
authors: O
authors: Farges
authors: Bertrand
authors: B
authors: Condat
authors: Dominique
authors: D
authors: Vidaud
authors: Michel
authors: M
authors: Vidaud
authors: Jian-Min
authors: JM
authors: Chen
authors: Béatrice
authors: B
authors: Parfait
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics*; D000328:Adult; D001483:Base Sequence; D002769:Cholelithiasis / Q000235:genetics*; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced / Q000235:genetics*; D002897:Chromosomes, Human, Pair 7; D055028:Comparative Genomic Hybridization; D003276:Contraceptives, Oral / Q000009:adverse effects*; D005260:Female; D005705:Gallbladder Diseases / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011248:Pregnancy Complications / Q000235:genetics*; D013577:Syndrome; D055815:Young Adult
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D003276:Contraceptives, Oral; C095122:multidrug resistance protein 3