ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy.
BACKGROUND
Intrahepatic cholestasis of pregnancy (ICP) affects approximately 0.7% of pregnancies in the UK and is associated with prematurity, fetal distress, and intrauterine death. Homozygous mutations in the ATP8B1 gene cause cholestasis with a normal serum gamma-glutamyl transpeptidase (gamma-GT), and have been reported in two forms of cholestasis: progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis (BRIC).


OBJECTIVE
To establish whether mutations in ATP8B1 are associated with ICP in British cases


METHODS
Sixteen well phenotyped women with ICP without raised gamma-GT were selected for sequence analysis. Subsequently, 182 patients and 120 controls were examined for the presence of the variants detected.


METHODS
All coding exons were sequenced in 16 cases. Eight ICP cases, including two women carrying a mutation, were investigated using in vivo hepatic (31)P magnetic resonance spectroscopy (MRS) RESULTS: Two heterozygous ATP8B1 transitions (208G>A and 2599C>T) that resulted in amino acid substitutions were identified; 208G>A was identified in three cases. MRS revealed an increased phosphodiester signal (Mann-Whitney U test, p = 0.03) and a decreased phosphomonoester/phosphodiester ratio (p = 0.04) in ICP cases compared with controls.


CONCLUSIONS
We were able to demonstrate ATP8B1 mutations in ICP. MRS studies suggest that susceptibility to ICP is associated with a relative rise in biliary phospholipid. These data also suggest that MRS may be used for non-invasive assessment of the liver and biliary constituents in cholestasis.
Müllenbach
R
R
Maternal and Fetal Disease Group, 3rd Floor IRDB, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
Bennett
A
A
Tetlow
N
N
Patel
N
N
Hamilton
G
G
Cheng
F
F
Chambers
J
J
Howard
R
R
Taylor-Robinson
S D
SD
Williamson
C
C
D000251:Adenosine Triphosphatases / Q000235:genetics*; D002780:Cholestasis, Intrahepatic / Q000235:genetics* / Q000378:metabolism; D004952:Esters / Q000378:metabolism; D005260:Female; D005820:Genetic Testing / Q000379:methods; D006579:Heterozygote; D006801:Humans; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation / Q000235:genetics*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism; D017421:Sequence Analysis
D004952:Esters; D000251:Adenosine Triphosphatases; C111067:ATP8B1 protein, human