ABCB11 – Benign Recurrent Intrahepatic Cholestasis Type 2

ABCB11 encodes the bile salt export pump (BSEP), essential for hepatocanalicular bile salt secretion. Benign recurrent intrahepatic cholestasis type 2 (BRIC2) is an autosomal recessive disorder characterized by intermittent cholestasis presenting with pruritus and jaundice. Multiple unrelated probands carrying biallelic ABCB11 variants establish a consistent link between gene dysfunction and episodic cholestasis.

Pedigree analyses confirm autosomal recessive inheritance. A Korean sib pair demonstrated segregation of compound heterozygous ABCB11 mutations with disease in one additional affected relative (PMID:30899697). Other adult-onset and pediatric cases carried biallelic variants without family history, consistent with full penetrance in homozygotes (PMID:31015375, PMID:38607191).

Across six probands, variants include missense, nonsense, splice-site, and synonymous but splice-disruptive alleles. A recurrent missense change, c.3148C>T (p.Arg1050Cys), impairs BSEP transport and recurs in BRIC2 patients (PMID:17855769). Novel splice-site variants such as c.2075+3A>G further emphasize allelic heterogeneity in BRIC2 (PMID:30899697).

Functional studies show BRIC2 mutants reach the canalicular membrane but exhibit partial taurocholate transport (A570T and R1050C retain ~50% of wild-type activity) (PMID:17855769). In vitro and clinical data demonstrate that 4-phenylbutyrate treatment restores cell-surface expression of hypomorphic variants and relieves cholestatic episodes in a refractory BRIC2 patient (PMID:26223708).

The preservation of BSEP localization in liver biopsies, coupled with residual transporter function, explains the benign, relapsing course of BRIC2 versus progressive familial intrahepatic cholestasis type 2 (PFIC2). These genotype–phenotype correlations enhance variant interpretation in diagnostic settings.

Integration of robust segregation data in six probands, concordant functional impairment, and therapeutic rescue supports a Strong clinical validity for ABCB11 in BRIC2. Genetic testing for ABCB11, notably c.3148C>T (p.Arg1050Cys), informs diagnosis, guides management, and enables accurate genetic counseling.

References

• Pediatrics • 2019 • Beyond an Obvious Cause of Cholestasis in a Toddler: Compound Heterozygosity for ABCB11 Mutations. PMID:31015375
• Pediatric gastroenterology, hepatology & nutrition • 2019 • Benign Recurrent Intrahepatic Cholestasis Type 2 in Siblings with Novel ABCB11 Mutations. PMID:30899697
• Hepatology research • 2016 • Successful treatment with 4-phenylbutyrate in a patient with benign recurrent intrahepatic cholestasis type 2 refractory to biliary drainage and bilirubin absorption. PMID:26223708
• American journal of physiology. Cell physiology • 2007 • Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases. PMID:17855769
• Alternative therapies in health and medicine • 2024 • A Rare Case of Benign Recurrent Intrahepatic Cholestasis Initially Diagnosed in Middle-age. PMID:38607191

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