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 contraceptivesinduced 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.

Genotype-phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: A study of 156 consecutive patients

“…In this context, high‐resolution gene dosage methodologies were used recently in 43 negative LPAC patients for heterozygous point or short insertion/deletion mutations. A partial or complete heterozygous deletion was detected in 7% of them …”

The Role of Canalicular ABC Transporters in Cholestasis

“…3) (Zhang, 1996). ABCB4 is predominantly expressed in the apical membrane of hepatocytes (Yoshikado et al, 2011;Pasmant et al, 2012), although low levels of mRNA transcripts have been detected in the adrenal glands, heart, striated muscles, tonsils, placenta, and brain Patel et al, 2003;Augustine et al, 2005;Kim et al, 2008;Cui et al, 2009). This expression pattern supports its role as the major canalicular PC transporter in humans.…”

“…The clinical relevance of this transport, however, has not been established. Other drugs, such as oral contraceptives and itraconazole, can inhibit ABCB4 activity, which may result in drug-induced liver damage (Yoshikado et al, 2011;Pasmant et al, 2012).…”

Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2‐deficient mice

“…In particular, lesions in the gene encoding multidrug resistance 3 P‐glycoprotein (MDR3, also known as ABCB4) result in abnormal excretion of biliary phosphatidylcholine and the onset of intrahepatic cholestasis . To date, more than 30 mutations in MDR3 have been reported that are causally associated with a variety of biliary diseases, including PFIC type 3 (PFIC3), intrahepatic cholestasis of pregnancy, low phospholipid‐associated cholelithiasis, anicteric cholestasis, oral contraceptive‐induced cholestasis, and cirrhosis …”