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Recessive Inheritance of Population‐Specific Intronic LINE ‐1 Insertion Causes a R otor Syndrome Phenotype
Author(s) -
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
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22745
Subject(s) - biology , genetics , retrotransposon , insertion , intron , slco1b1 , exon , population , gene , stop codon , transposable element , mutation , genome , single nucleotide polymorphism , genotype , demography , sociology
Sequences of long‐interspersed elements ( LINE ‐1, L 1) make up ∼17% of the human genome. De novo insertions of retrotransposition‐active L 1s 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 OATP 1 B 1 and OATP 1 B 3 causes a benign recessive disease presenting with conjugated hyperbilirubinemia, R otor syndrome. Here, we examined SLCO1B1 and SLCO1B3 genes in six J apanese diagnosed with R otor syndrome on the basis of laboratory data and laparoscopy. All six J apanese patients were homozygous for the c.1738 C > T nonsense mutation in SLCO1B1 and homozygous for the insertion of a ∼6.1‐kbp L 1 retrotransposon in intron 5 of SLCO1B3 , which altogether make up a J apanese‐specific haplotype. RNA analysis revealed that the L 1 insertion induced deleterious splicing resulting in SLCO1B3 transcripts lacking exon 5 or exons 5–7 and containing premature stop codons. The expression of OATP 1 B 1 and OATP 1 B 3 proteins was not detected in liver tissues. This is the first documented case of a population‐specific polymorphic intronic L 1 transposon insertion contributing to molecular etiology of recessive genetic disease. Since L 1 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.