A Paradigm for the Genetics of Adult Cholestatic Syndromes

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MDR3 (ABCB4) Defects: A

Paradigm for the Genetics of Adult Cholestatic

Syndromes

Trauner,

Fickert, Wagner

Laboratory of Experimental and

Molecular Hepatology, Division of Gastroenterology and Hepatology, Department

of Internal Medicine, Medical University of Graz, Austria

ABSTRACT

Because

ATP-binding cassette (ABC) transporters are important for normal bile

secretion, hereditary and acquired ABC transporter defects play a central role

in the pathogenesis of cholestasis. Defects of the phospholipid

export pump MDR3

(ABCC4)

result in impaired biliary excretion of phosphatidylcholine

and a variety of cholestatic syndromes ranging from

progressive familial intrahepatic cholestasis in

neonates to biliary cirrhosis in adults. Moreover, MDR3 mutations predispose to

cholestasis of pregnancy and drug-induced cholestasis. Because

Mdr2

(rodent orthologue of human MDR3)

knockout mice develop sclerosing cholangitis,

it is attractive to speculate that MDR3 defects could also play

an important role in cholangiopathies in humans. Indeed, MDR3 variants could play a

role as modifier gene in primary biliary cirrhosis and primary sclerosing cholangitis, but their

exact role needs further clarification. Impaired

biliary phosphatidylcholine excretion has also been

reported in total parenteral nutrition-induced cholestasis and bile duct injury following liver

transplantation, but a genetic basis for these findings remains to be explored. Several drugs for the treatment of cholestatic

liver diseases target MDR3

expression and function, further underscoring the clinical significance of this

transport system.

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