title: Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy.
abstract: Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic condition that may affect women during the third trimester of pregnancy. Symptoms experienced by these women generally resolve spontaneously following delivery, but prior to delivery the fetus is at increased risk of intrauterine distress and sudden intrauterine death. The genetic etiology of most cases of ICP is unknown, although heterozygous carriers of mutations causing progressive familial intrahepatic cholestasis (PFIC) diseases may experience ICP. When examining linkage to known cholestasis genes, affected members of four Finnish ICP families shared haplotypes around ATP8B1, the gene responsible for PFIC1. This gene was subsequently screened in 176 familial and sporadic ICP patients. A total of 17 sequence changes were detected, five exonic and 12 intronic. No intronic change was associated with ICP in sporadic cases. Four intronic changes segregated with ICP in three families, a different change in each of two families and three changes in another family, although the significance of this is currently unknown. Three exonic changes were nonsynonymous, one (in exon 23) is probably a polymorphism while two predict novel amino-acid replacements (N45T and K203R). These changes, in exons 2 and 7, were detected in one individual each, and may have predisposed these individuals to ICP. In conclusion, although the exon 2 and 7 changes may have functioned as risk alleles, ATP8B1 is probably not a major gene contributing to the occurrence of ICP.
authors.affiliation: Folkhälsan Institute of Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland. jodie.painter@helsinki.fi
authors.forename: Jodie N
authors.initials: JN
authors.lastname: Painter
authors.forename: Miia
authors.initials: M
authors.lastname: Savander
authors.forename: Anne
authors.initials: A
authors.lastname: Ropponen
authors.forename: Nina
authors.initials: N
authors.lastname: Nupponen
authors.forename: Seija
authors.initials: S
authors.lastname: Riikonen
authors.forename: Olavi
authors.initials: O
authors.lastname: Ylikorkala
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D002780:Cholestasis, Intrahepatic / Q000453:epidemiology / Q000235:genetics*; D005091:Exons; D005260:Female; D018740:Genetic Heterogeneity; D008040:Genetic Linkage / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications / Q000453:epidemiology / Q000209:etiology*
chemical_list: D000251:Adenosine Triphosphatases; C111067:ATP8B1 protein, human