Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy

✍ Scribed by Gudrun Schneider; Teresa C. Paus; Gerd A. Kullak-Ublick; Peter J. Meier; Thomas F. Wienker; Thomas Lang; Patricia van de Vondel; Tilman Sauerbruch; Christoph Reichel

• Book ID: 102850289
• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 601 KB
• Volume: 45
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.21500

✦ Synopsis

Intrahepatic cholestasis of pregnancy (ICP) is defined as pruritus and elevated bile acid serum concentrations in late pregnancy. Splicing mutations have been described in the multidrug resistance p-glycoprotein 3 (MDR3, ABCB4) gene in up to 20% of ICP women. Pedigrees studied were not large enough for linkage analysis. Ninety-seven family members of a woman with proven ICP were asked about pruritus in earlier pregnancies, birth complications and symptomatic gallstone disease. The familial cholestasis type 1 (FIC1, ATP8B1) gene, bile salt export pump (BSEP, ABCB11) and MDR3 gene were analyzed in 55 relatives. We identified a dominant mode of inheritance with female restricted expression and a new intronic MDR3 mutation c.3486؉5G>A resulting in a 54 bp (3465-3518) inframe deletion via cryptic splicing site activation. Linkage analysis of the ICP trait versus this intragenic MDR3 variant yielded a LOD score of 2.48. A Bayesian analysis involving MDR3, BSEP, FIC1 and an unknown locus gave a posterior probability of >0.9966 in favor of MDR3 as causative ICP locus. During the episode of ICP the median ␥-glutamyl transpeptidase (␥-GT) activity was 10 U/l (95% CI, 6.9 to 14.7 U/l) in the index woman. Four stillbirths were reported in seven heterozygous women (22 pregnancies) and none in five women (14 pregnancies) without MDR3 mutation. Symptomatic gallstone disease was more prevalent in heterozygous relatives (7/21) than in relatives without the mutation (1/34), (P ‫؍‬ 0.00341). Conclusion: This study demonstrates that splicing mutations in the MDR3 gene can cause ICP with normal ␥-GT and may be associated with stillbirths and gallstone disease. (HEPATOLOGY 2007;45:150-158.)

I ntrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder of pregnant women which was first described by Ahlfeld in 1883. The incidence of ICP in Europe is approximately 0.1 to 1.5% of pregnancies. In contrast, incidence rates as high as 16% have been described in Chile and Bolivia. ICP is generally characterized by a benign course of disease with a good prognosis. However, vehement itching, jaundice and fat malabsorption may impair the mother's quality of life. On the other hand, an increased perinatal fetal risk with possible lethal outcome has been described. Early studies on ICP considered its etiology as idiopathic. 12 However, even in these early studies several cases of familial recurrent ICP were identified in various regions of the world. Reyes et al. described a family from Chile in which 10 of 32 multiparous women developed ICP over two generations. In 1983 Holzbach et al. presented their analysis on dominant familial ICP in three generations of a pedigree comprising more than 50 individuals. 14 These studies were mainly descriptive and did not allow conclusions on the pathophysiology of ICP. This changed when Jacquemin and co-worker discovered that heterozygosity for a non-sense mutation in the MDR3 alias name ABCB4 gene was associated with ICP in family members of a child with a severe form of progressive familial intrahepatic cholestasis type three (PFIC 3). 10 This observation fostered the assumption that MDR3 gene variants may be associated with a familial