ABCB11 – Progressive Familial Intrahepatic Cholestasis Type 2

Progressive familial intrahepatic cholestasis type 2 (PFIC2) is an autosomal recessive disorder caused by biallelic pathogenic variants in ABCB11, which encodes the canalicular bile salt export pump (BSEP). Affected infants present with low–gamma‐glutamyltransferase cholestasis, severe pruritus, malabsorption and progressive hepatic fibrosis leading to cirrhosis. Absent or reduced canalicular BSEP staining on liver biopsy establishes the clinical diagnosis and prompts genetic testing for ABCB11 variants.

Genetic studies have identified over 100 distinct ABCB11 mutations in more than 109 families worldwide, with >200 affected individuals carrying biallelic changes [PMID:18395098]. Variants include missense substitutions, frameshifts, nonsense and splice‐site mutations. The recurrent European variant c.1445A>G (p.Asp482Gly) is detected in ~45% of families and correlates with absent BSEP immunostaining, whereas c.150+3A>C and other splice‐site changes lead to exon skipping and loss of function [PMID:16039748]. Population‐specific alleles such as c.386G>A (p.Cys129Tyr) in Japanese patients demonstrate impaired membrane trafficking and reduced bile salt transport [PMID:29507376].

Functional assays in polarized hepatocellular and MDCK cells have shown that PFIC2‐associated missense mutations impair BSEP maturation, stability and canalicular targeting. The D482G mutant exhibits temperature‐sensitive folding and partial trafficking rescue at 30 °C [PMID:14672610], whereas p.Thr1210Pro mislocalizes to the ER but can be retargeted to the canalicular membrane by 4‐phenylbutyrate treatment, resulting in improved bile flow and clinical parameters [PMID:22609309]. A high‐resolution cryo‐EM structure combined with in‐cell thermal shift assays has mapped a cluster of destabilizing variants at the NBD2–ICL2 interface, offering a mechanistic framework for misfolding and opportunities for small-molecule correctors [PMID:40195555]. A knock-in mouse model of the E297G variant recapitulates cholestasis and hepatotoxicity, validating the in vivo relevance of trafficking defects [PMID:40513781].

Although liver transplantation is often curative, rare cases of post-transplant recurrence due to anti-BSEP alloantibodies highlight an immunologic mechanism of cholestasis that does not compromise the genetic association (e.g., autoantibody–mediated BSEP inhibition) [PMID:19642168]. These cases underscore the need for ongoing surveillance and immunomodulatory therapy in transplant recipients.

In summary, definitive genetic and experimental evidence confirms that biallelic loss-of-function variants in ABCB11 cause PFIC2 through a haploinsufficiency mechanism. Genetic diagnosis directs counseling, guides the application of mutation-specific chaperone therapy and informs decisions regarding biliary diversion or transplantation. Key Take-home: Early identification of ABCB11 variants enables precision management of PFIC2, including targeted pharmacotherapy and timely surgical intervention.

References

• Gastroenterology • 2008 • Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. [PMID:18395098]
• Journal of Human Genetics • 2018 • Clinical phenotype and molecular analysis of a homozygous ABCB11 mutation responsible for progressive infantile cholestasis. [PMID:29507376]
• Journal of Hepatology • 2012 • Successful mutation-specific chaperone therapy with 4-phenylbutyrate in a child with progressive familial intrahepatic cholestasis type 2. [PMID:22609309]
• Communications Biology • 2025 • A structural and mechanistic model for BSEP dysfunction in PFIC2 cholestatic disease. [PMID:40195555]
• Hepatology • 2009 • De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis. [PMID:19642168]

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