The patient was investigated for the presence of cholestasis and acholic stool by examination of neonatal sclerosing cholangitis (DCDC2 gene), alpha-1 antitrypsin deficiency (A1AD; SERPINA1 gene), Alagille syndrome (JAG1 gene), progressive familial intrahepatic cholestasis type 3 (ABCB4
gene), and cystic fibrosis (CFTR gene); no mutation was identified.
, an ABC transporter gene encoding hepatic microtubule flinty flippase, was knocked out in mice, the secretion of bile acid and phospholipids was inhibited.
Multidrug resistance protein 3 (MDR3, gene ABCB4
) is understood to act as a floppase, which translocates phospholipids from the inner to the outer leaflet of the lipid bilayer of the canalicular membrane .
Familial intrahepatic cholestasis (FIC) comprises a group of rare cholestatic liver diseases associated with canalicular transport defects resulting predominantly from mutations in ATP8B1, ABCB11 and ABCB4
. Phenotypes range from benign recurrent intrahepatic cholestasis (BRIC), to progressive FIC (PFIC).
Therefore, hereditary CLD in children, which result from mutations of genes involved in bile acid and phosphatidylcholine transport, such as ATP8B1 [4, 5], ABCB11 , and ABCB4
, are relatively easy to diagnose.
One recent example is the repurposing of the CFTR/ABCC7-specific potentiator, ivacaftor (Kalydeco[R]), for patients with mutations in a homologous ABC protein: ABCB4
CLA isomers have been found to act as PPAR ligands and shown to be involved in the inhibition of transcription of genes including TNF , NFKB1 , and NR1I3  as well as transactivation: TGFB1 , BRCA1 , PTEN , p21/WAF1/CDKN1A , CEBPA , ABCB4
, and AOX .
Genotypes of mice included in the MRR experiments were confirmed by polymerase chain reaction (PCR) of tail DNA using neo (5'-CTTGGGTGGAGAGGCTATTC-3' and 5'-AGGTGAGATGACAGGAGATC-3') and Abcb4
(5'-CACTTGGACCTGAGGCTGTG-3' and 5'-TCAGGACTCCGCTATAACGG-3') specific primer pairs.
A genetic basis for their disorder is highly likely, perhaps MDR3 (ABCB4
) deficiency, which has been associated with gallstones and intrahepatic cholestasis of pregnancy, among other problems (9).
Heterogeneous mutations in MDR3 (ABCB4
) gene are reported in patients with ICP.2 In Caucasian ICP patients,16% such mutations have been demonstrated.3
and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population.
Their function requires significant energy expenditure in the form of adenosine triphosphate (ATP), and most transporters belong to the ATP-binding cassette (ABC) transporter superfamily such as ATP8B1 (ATPase class I type 8B1), ABCB11 (ABC, subfamily B, member 11), and ABCB4
(ABC, subfamily B, member 4), all of which are responsible for 3 types of PFIC, respectively.