ABCC2 – Dubin-Johnson Syndrome

Dubin-Johnson syndrome is a rare autosomal recessive liver disorder caused by biallelic loss-of-function variants in ABCC2, leading to chronic predominantly conjugated hyperbilirubinemia and black liver pigmentation. The clinical validity of this gene–disease pair is classified as Strong, based on over 100 probands from more than 50 unrelated families, with multi-ethnic founder mutations and consistent experimental findings supporting pathogenicity.

1. Assess Clinical Validity

ClinGen Classification: Strong

Rationale: >100 probands across >50 unrelated families, multi-family segregation, and concordant in vivo and in vitro functional studies support a definitive association.

2. Genetic Evidence

Inheritance is autosomal recessive, with compound heterozygous and homozygous presentations. Segregation has been documented in at least 19 affected relatives within multiplex pedigrees. Case reports and series describe >78 distinct ABCC2 variants: nonsense (e.g., c.1963C>T (p.Arg655Ter)), frameshift (c.513del (p.Tyr172LeufsTer6)), splice-site (c.2439+2T>C), and missense (c.2302C>T (p.Arg768Trp)) classes. Recurrent/founder alleles include p.Ile1173Phe in Iranian Jews (22 homozygotes from 13 families) and p.Arg1150His in Moroccan Jews (5 homozygotes from 4 families) ([PMID:11477083]). The variant c.2302C>T (p.Arg768Trp) was homozygous in a Caucasian patient with hallmark conjugated hyperbilirubinemia ([PMID:12942343]).

3. Functional / Experimental Evidence

The TR⁻ rat lacking the orthologous cmoat transporter exhibits phenotypic concordance with human DJS, demonstrating impaired canalicular efflux and hyperbilirubinemia ([PMID:9185779]). Cellular expression studies show that p.Arg768Trp results in Endo H-sensitive precursor degradation and failure to mature or localize to the canalicular membrane ([PMID:12395335]). Site-directed mutagenesis of founder I1173F and R1150H alleles impairs both MRP2 maturation (ER retention) and transport activity in HEK-293 cells ([PMID:11477083]). Broad substrate profiling confirms loss of ATP-dependent export of bilirubin conjugates ([PMID:10581368]).

4. Conflicting Evidence

The R1066X allele, initially reported in a Caucasian patient, was not detected in six Japanese DJS patients, indicating population specificity rather than a disputed association ([PMID:10319416]). No studies refute the core AR loss-of-function mechanism.

5. Integration & Conclusion

ABCC2 encodes MRP2, an ATP-dependent canalicular efflux pump for organic anion conjugates. Pathogenic variants cause defective protein processing or transport activity, leading to conjugated hyperbilirubinemia without progression to end-stage liver disease. Genetic testing for ABCC2 variants provides definitive diagnosis, guides differential evaluation of neonatal cholestasis, and informs drug dosing due to altered transporter function.

Key Take-home: ABCC2 genetic analysis is clinically useful for diagnosing Dubin-Johnson syndrome and anticipating pharmacokinetic implications.

References

• Hepatology (Baltimore, Md.) • 1997 • A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. PMID:9185779
• Journal of human genetics • 2003 • Homozygous mutation Arg768Trp in the ABC-transporter encoding gene MRP2/cMOAT/ABCC2 causes Dubin-Johnson syndrome in a Caucasian patient. PMID:12942343
• The Journal of biological chemistry • 2001 • Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome. PMID:11477083
• Hepatology (Baltimore, Md.) • 2002 • Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome. PMID:12395335
• Biochimica et biophysica acta • 1999 • Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. PMID:10581368
• Biochemistry and molecular biology international • 1999 • Absence of R1066X mutation in six Japanese patients with Dubin-Johnson syndrome. PMID:10319416
• Gastroenterology • 1999 • Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome. PMID:10464142

Evidence Based Scoring (AI generated)