SLCO1B3 – Rotor syndrome

Rotor syndrome is a rare, benign autosomal recessive hyperbilirubinemia characterized by chronic conjugated bilirubin elevation (HP:0002908) due to impaired hepatic bilirubin reuptake. Digenic loss-of-function (LoF) variants in both SLCO1B1 and SLCO1B3 disrupt the OATP1B1/B3 transporters, defining the molecular basis of the disorder. Genetic confirmation is critical for accurate diagnosis and management, distinguishing Rotor syndrome from similar cholestatic diseases.

Autosomal recessive digenic inheritance of SLCO1B3 is established in multiple unrelated cohorts. Two Chinese patients were found to carry a novel exon 4 inversion in SLCO1B3 intron 3 and the nonsense variant c.757C>T (p.Arg253Ter), confirmed by splicing assays and genome walking (PMID:32082363). Six Japanese individuals share a population-specific haplotype with homozygous c.1738C>T (p.Arg580Ter) in SLCO1B1 and a LINE-1 insertion in SLCO1B3 intron 5, leading to aberrant splicing and premature stop codons (PMID:25546334).

An initial case, misdiagnosed as Dubin–Johnson syndrome, revealed a homozygous deletion of SLCO1B3 exons 4–16 on exome sequencing and panel testing, solidifying Rotor syndrome diagnosis (PMID:36157610). This underscores the value of comprehensive genetic testing in suspected conjugated hyperbilirubinemia.

Variant spectrum includes nonsense mutations (c.757C>T (p.Arg253Ter); c.1738C>T (p.Arg580Ter)), splice-site/inversion (c.1747+1G>A and exon 4 inversion), large deletions, and intronic LINE-1 insertions, with recurrent founder alleles in East Asian populations contributing to a defined molecular signature.

Functional studies demonstrate that the exon 4 inversion in SLCO1B3 causes exon skipping, frameshift, and premature termination codon, abolishing transporter expression in hepatocytes ([PMID:32082363]). RNA analyses in Japanese patients confirmed similar exon losses and undetectable OATP1B3 protein in liver tissue, concordant with the human phenotype ([PMID:25546334]).

Segregation data are limited; heterozygous carriers remain asymptomatic. However, the replication of LoF variants in multiple unrelated probands and consistent functional assays support a definitive gene–disease relationship for SLCO1B3 in Rotor syndrome.

Key take-home: Biallelic SLCO1B3 LoF variants, in concert with SLCO1B1 lesions, are definitively causal for Rotor syndrome. Genetic testing of SLCO1B3 should be incorporated into diagnostic workflows to provide accurate diagnosis, patient reassurance, and avoidance of invasive procedures.

References

• Case reports in gastroenterology • 2022 • Rotor Syndrome Presenting as Dubin-Johnson Syndrome. PMID:36157610
• Frontiers in genetics • 2019 • Insertion of LINE-1 Retrotransposon Inducing Exon Inversion Causes a Rotor Syndrome Phenotype. PMID:32082363
• Human Mutation • 2015 • Recessive inheritance of population-specific intronic LINE-1 insertion causes a rotor syndrome phenotype. PMID:25546334

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