Recessive inheritance of population-specific intronic LINE-1 insertion causes a rotor syndrome phenotype

Hum Mutat. 2015 Mar;36(3):327-32. doi: 10.1002/humu.22745.


Sequences of long-interspersed elements (LINE-1, L1) make up ∼17% of the human genome. De novo insertions of retrotransposition-active L1s can result in genetic diseases. It has been recently shown that the homozygous inactivation of two adjacent genes SLCO1B1 and SLCO1B3 encoding organic anion transporting polypeptides OATP1B1 and OATP1B3 causes a benign recessive disease presenting with conjugated hyperbilirubinemia, Rotor syndrome. Here, we examined SLCO1B1 and SLCO1B3 genes in six Japanese diagnosed with Rotor syndrome on the basis of laboratory data and laparoscopy. All six Japanese patients were homozygous for the c.1738C>T nonsense mutation in SLCO1B1 and homozygous for the insertion of a ∼6.1-kbp L1 retrotransposon in intron 5 of SLCO1B3, which altogether make up a Japanese-specific haplotype. RNA analysis revealed that the L1 insertion induced deleterious splicing resulting in SLCO1B3 transcripts lacking exon 5 or exons 5-7 and containing premature stop codons. The expression of OATP1B1 and OATP1B3 proteins was not detected in liver tissues. This is the first documented case of a population-specific polymorphic intronic L1 transposon insertion contributing to molecular etiology of recessive genetic disease. Since L1 activity in human genomes is currently seen as a major source of individual genetic variation, further investigations are warranted to determine whether this phenomenon results in other autosomal-recessive diseases.

Keywords: LINE-1; OATP; conjugated hyperbilirubinemia; polymorphic insertion.

MeSH terms

  • Adult
  • Female
  • Genetic Diseases, Inborn / genetics*
  • Humans
  • Hyperbilirubinemia, Hereditary / genetics*
  • Introns*
  • Liver-Specific Organic Anion Transporter 1
  • Long Interspersed Nucleotide Elements*
  • Male
  • Middle Aged
  • Organic Anion Transporters / genetics
  • Organic Anion Transporters, Sodium-Independent / genetics
  • Phenotype
  • Retroelements
  • Solute Carrier Organic Anion Transporter Family Member 1B3


  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Independent
  • Retroelements
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3