SLCO1B1 – Rotor Syndrome

Rotor syndrome is a rare autosomal recessive disorder characterized by chronic conjugated hyperbilirubinemia due to impaired hepatic bilirubin reuptake. Biallelic loss-of-function variants in the sinusoidal uptake transporter SLCO1B1, often in combination with SLCO1B3 defects, abolish OATP1B1/B3 function and underlie the disease mechanism ([PMID:36157610]). This summary integrates clinical validity, genetic evidence, and functional data to support diagnostic decision-making and publication.

Clinical validity of the SLCO1B1–Rotor syndrome association is classified as Definitive. Ten probands from unrelated families harboring biallelic SLCO1B1 variants have been reported, all showing consistent autosomal recessive inheritance and concordant functional data ([PMID:36157610]; [PMID:39071607]; [PMID:32082363]; [PMID:25546334]).

Genetic evidence is Strong: affected individuals present with homozygous or compound heterozygous variants, including recurring nonsense mutations such as c.1738C>T (p.Arg580Ter) and structural LINE-1–induced inversions disrupting SLCO1B3 ([PMID:39071607]; [PMID:32082363]; [PMID:25546334]). No additional affected relatives beyond probands have been documented.

Variant spectrum comprises:

• Nonsense: c.1738C>T (p.Arg580Ter) ([PMID:39071607]; [PMID:25546334])
• Nonsense: c.757C>T (p.Arg253Ter) ([PMID:32082363])
• LINE-1–mediated exon inversion: SLCO1B3 intron 3 ([PMID:32082363])

Functional evidence is Moderate: splicing assays confirmed exon 4 inversion induced by LINE-1 insertion in SLCO1B3 leading to premature stop codons ([PMID:32082363]), and OATP1B1/B3 knockout or humanized mouse models recapitulate conjugated hyperbilirubinemia ([PMID:25546334]).

No studies refute this association. In sum, SLCO1B1 loss-of-function variants definitively cause Rotor syndrome by abolishing hepatocellular bilirubin uptake. Genetic testing for SLCO1B1 should be incorporated into diagnostic panels for conjugated hyperbilirubinemia and carrier screening.

Key Take-home: Biallelic SLCO1B1 variants are a definitive cause of Rotor syndrome and warrant inclusion in genetic testing for hereditary hyperbilirubinemia.

References

• Case Reports in Gastroenterology • 2022 • Rotor Syndrome Presenting as Dubin-Johnson Syndrome. PMID:36157610
• Heliyon • 2024 • A pedigree analysis of Rotor hyperbilirubinemia combined with hepatitis B virus infection in a SLCO1B1 and SLCO1B3 gene mutations patient. PMID:39071607
• 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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