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 a...

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Published in:Human mutation 2015-03, Vol.36 (3), p.327-332
Main Authors: Kagawa, Tatehiro, Oka, Akira, Kobayashi, Yoshinao, Hiasa, Yoichi, Kitamura, Tsuneo, Sakugawa, Hiroshi, Adachi, Yukihiko, Anzai, Kazuya, Tsuruya, Kota, Arase, Yoshitaka, Hirose, Shunji, Shiraishi, Koichi, Shiina, Takashi, Sato, Tadayuki, Wang, Ting, Tanaka, Masayuki, Hayashi, Hideki, Kawabe, Noboru, Robinson, Peter N., Zemojtel, Tomasz, Mine, Tetsuya
Format: Article
Language:English
Subjects:
Adult
conjugated hyperbilirubinemia
Female
Genetic Diseases, Inborn - genetics
Genetic disorders
Genotype & phenotype
Humans
Hyperbilirubinemia, Hereditary - genetics
Introns
LINE-1
Long Interspersed Nucleotide Elements
Male
Medical research
Middle Aged
Mutation
OATP
Organic Anion Transporters - genetics
Organic Anion Transporters, Sodium-Independent - genetics
Phenotype
polymorphic insertion
Retroelements
Solute Carrier Organic Anion Transporter Family Member 1b1
Solute Carrier Organic Anion Transporter Family Member 1B3
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Summary: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. We demonstrate that Japanese patients with Rotor syndrome have a unique homozygous JP haplotype including LINE‐1 retrotransposon insertion in SLCO1B3. This is the first example of a homozygous L1 insertion contributing to autosomal‐recessive disease.
ISSN:1059-7794
1098-1004
DOI:10.1002/humu.22745