ABCB4 gene mutations leading to a multidrug resistance (MDR)3-P-glycoprotein deficiency are related to, among other diseases, recurrent cholelithiasis.
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).
In PS bile acid concentration correlated with gallstone plant sterols (R = 0.83, P < 0.0001), and ABCG5 expression with ABCB11 expression (R = 0.27, P = 0.03).
In our study we investigated the contribution of heterozygosity for common variations considered either potentially pathogenic or susceptibility alleles for cholesterol cholelithiasis in adults (c.523A>G (p.Thr175Ala) and c.1954A>G (p.Arg652Gly) in ABCB4, c.1331T>C (p.Val444Ala) in ABCB11 and c.55 G>C (p.Asp19His) in ABCG8) to the aetiology of paediatric idiopathic gallstone disease.
Thus, ICP may unmask an underlying MDR3 defect, which may predispose to development of hepatobiliary diseases such as gallstone disease, liver fibrosis/cirrhosis, as well as hepatobiliary malignancies.
The young age of the patient, recurrence of gallstones after cholecystectomy and intrahepatic gallstones suggested a subtype of the low-phospholipid associated cholelithiasis syndrome, a monogenic form of cholesterol cholelithiasis due to variations of the ABCB4 gene that encodes the canalicular phospholipid transporter MDR3.
A smaller group of patients might develop gallstones primarily due low phosphatidylcholine concentrations in bile as a result of loss-of-function mutations of the ABCB4 transporter (low phospholipid-associated cholelithiasis syndrome).
48 mutations of MDR3 gene have been reported in humans to date, from which 43 (89.5%) in the coding region, and 5 splice site mutations have been associated to cholesterol cholelithiasis.
ABCB4 gene mutations leading to a multidrug resistance (MDR)3-P-glycoprotein deficiency are related to, among other diseases, recurrent cholelithiasis.
Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of ABCB4 mutations and low biliary phospholipid concentration with symptomatic and recurring cholelithiasis.
Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of ABCB4 mutations and low biliary phospholipid concentration with symptomatic and recurring cholelithiasis.
A second ABC transporter, the hepatic phosphatidylcholine translocase ABCB4, increases the risk for gallstone disease, gallbladder cancer and chronic liver diseases in general, whereas the common PNPLA3 risk variant p.I148M decreases gallstone risk.
In our study we investigated the contribution of heterozygosity for common variations considered either potentially pathogenic or susceptibility alleles for cholesterol cholelithiasis in adults (c.523A>G (p.Thr175Ala) and c.1954A>G (p.Arg652Gly) in ABCB4, c.1331T>C (p.Val444Ala) in ABCB11 and c.55 G>C (p.Asp19His) in ABCG8) to the aetiology of paediatric idiopathic gallstone disease.
This study demonstrates that splicing mutations in the MDR3 gene can cause ICP with normal gamma-GT and may be associated with stillbirths and gallstone disease.
Whereas rare mutations of this transporter were known to cause progressive familial intrahepatic cholestasis, the genome-wide association studies in Iceland find the common ABCB4 variant c.711A>T to be a general risk factor for elevated aminotransferases and higher impact variants to be potential determinants of early-onset gallstone disease, cholestasis of pregnancy, liver cirrhosis, and hepatobiliary cancer.