title: Recessive inheritance of population-specific intronic LINE-1 insertion causes a rotor syndrome phenotype.
abstract: 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.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Tatehiro
authors.initials: T
authors.lastname: Kagawa
authors.forename: Akira
authors.initials: A
authors.lastname: Oka
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hiasa
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Kitamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakugawa
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Adachi
authors.forename: Kazuya
authors.initials: K
authors.lastname: Anzai
authors.forename: Kota
authors.initials: K
authors.lastname: Tsuruya
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Arase
authors.forename: Shunji
authors.initials: S
authors.lastname: Hirose
authors.forename: Koichi
authors.initials: K
authors.lastname: Shiraishi
authors.forename: Takashi
authors.initials: T
authors.lastname: Shiina
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Sato
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tanaka
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Noboru
authors.initials: N
authors.lastname: Kawabe
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
authors.forename: Tomasz
authors.initials: T
authors.lastname: Zemojtel
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mine
mesh_terms: D000328:Adult; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006801:Humans; D006933:Hyperbilirubinemia, Hereditary / Q000235:genetics*; D007438:Introns; D027381:Liver-Specific Organic Anion Transporter 1; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D010641:Phenotype; D018626:Retroelements; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D018626:Retroelements; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
keywords: LINE-1; OATP; conjugated hyperbilirubinemia; polymorphic insertion