ABCB4 – Progressive Familial Intrahepatic Cholestasis Type 3

Progressive Familial Intrahepatic Cholestasis Type 3 (PFIC3; MONDO:0011214) is an autosomal recessive hepatobiliary disease caused by biallelic mutations in ABCB4 (HGNC:45; ABCB4), which encodes the phosphatidylcholine floppase MDR3. Affected individuals present in infancy or childhood with pruritus, elevated gamma-glutamyltransferase, cholestasis and progressive biliary cirrhosis.

1. Clinical Validity

The association between ABCB4 and PFIC3 is classified as Strong. Thirty-one unrelated patients harboring biallelic ABCB4 mutations have been documented, including homozygous and compound heterozygous alleles with consistent AR inheritance ([PMID:11313315]). Two brothers in a Portuguese family segregated the same ABCB4 variants with concordant PFIC3 phenotype ([PMID:26699824]). Functional studies across multiple reports demonstrate concordant loss of MDR3 activity, meeting ClinGen criteria for strong gene–disease validity.

2. Genetic Evidence

ABCB4-associated PFIC3 follows autosomal recessive inheritance with both homozygous and compound heterozygous presentations. Genetic studies have identified at least 16 distinct pathogenic alleles, including nonsense, frameshift and missense variants altering critical domains of MDR3. A total of 31 probands have been reported with pathogenic ABCB4 variants ([PMID:11313315]), and segregation of two additional affected siblings in one family supports linkage ([PMID:26699824]). Variant spectrum includes missense (e.g., c.3691C>T (p.His1231Tyr)), nonsense, splice-site and small deletions, with recurrent founder alleles in specific populations. Reported carrier frequencies in adult cohorts with cholestatic phenotypes reach up to 17.6% in primary biliary cirrhosis and 50% in intrahepatic cholestasis of pregnancy.

3. Functional Evidence

Loss of function is the primary mechanism, with in vitro assays demonstrating impaired ATP-hydrolysis and phosphatidylcholine transport for multiple variants. The p.His1231Tyr variant disrupts the conserved H-loop, abolishing ATPase activity in yeast expression ([PMID:22766396]). Recent studies show functional rescue of ATP-binding site mutants by the CFTR potentiator ivacaftor, restoring MDR3 canalicular localization and activity ([PMID:36674751]). Animal and cell models confirm that MDR3 deficiency leads to bile phospholipid paucity and progressive cholestasis.

4. Integration and Utility

Genetic testing for ABCB4 is essential for diagnosis of PFIC3, informs prognosis and guides therapy such as ursodeoxycholic acid and potential pharmacological chaperones. Functional assays elucidate variant pathogenicity and may enable genotype-directed treatment. Early identification of ABCB4 mutations can prevent misdiagnosis (e.g., as Wilson disease) and optimize clinical management.

Key Take-Home: ABCB4 biallelic mutations cause PFIC3 via MDR3 loss of function; combined genetic and functional evidence supports strong clinical validity, underpinning diagnostic testing and emerging targeted therapies.

References

• Gastroenterology • 2001 • The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. PMID:11313315
• Digestive and Liver Disease • 2016 • Elevation of gamma-glutamyl transferase in adult: Should we think about progressive familiar intrahepatic cholestasis? PMID:26699824
• Gene • 2012 • The histidine-loop is essential for transport activity of human MDR3. A novel mutation of MDR3 in a patient with progressive familial intrahepatic cholestasis type 3. PMID:22766396
• International Journal of Molecular Sciences • 2023 • Ivacaftor-Mediated Potentiation of ABCB4 Missense Mutations Affecting Critical Motifs of the NBDs: Repositioning Perspectives for Hepatobiliary Diseases. PMID:36674751

Evidence Based Scoring (AI generated)