A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter

Junji Umeno, Tadakazu Hisamatsu, Motohiro Esaki, Atsushi Hirano, Naoya Kubokura, Kouichi Asano, Shuji Kochi, Shunichi Yanai, Yuta Fuyuno, Katsuyoshi Shimamura, Naoki Hosoe, Haruhiko Ogata, Takashi Watanabe, Kunihiko Aoyagi, Hidehisa Ooi, Kenji Watanabe, Shigeyoshi Yasukawa, Fumihito Hirai, Toshiyuki Matsui, Mitsuo IidaTsuneyoshi Yao, Toshifumi Hibi, Kenjiro Kosaki, Takanori Kanai, Takanari Kitazono, Takayuki Matsumoto

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Previously, we proposed a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine as chronic nonspecific multiple ulcers of the small intestine (CNSU). By whole-exome sequencing in five Japanese patients with CNSU and one unaffected individual, we found four candidate mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. The pathogenicity of the mutations was supported by segregation analysis and genotyping data in controls. By Sanger sequencing of the coding regions, 11 of 12 other CNSU patients and 2 of 603 patients with a diagnosis of Crohn’s disease were found to have homozygous or compound heterozygous SLCO2A1 mutations. In total, we identified recessive SLCO2A1 mutations located at seven sites. Using RT-PCR, we demonstrated that the identified splice-site mutations altered the RNA splicing, and introduced a premature stop codon. Tracer prostaglandin E2 uptake analysis showed that the mutant SLCO2A1 protein for each mutation exhibited impaired prostaglandin transport. Immunohistochemistry and immunofluorescence analyses revealed that SLCO2A1 protein was expressed on the cellular membrane of vascular endothelial cells in the small intestinal mucosa in control subjects, but was not detected in affected individuals. These findings indicate that loss-of-function mutations in the SLCO2A1 gene encoding a prostaglandin transporter cause the hereditary enteropathy CNSU. We suggest a more appropriate nomenclature of “chronic enteropathy associated with SLCO2A1 gene” (CEAS).

Original languageEnglish
Article numbere1005581
JournalPLoS genetics
Volume11
Issue number11
DOIs
Publication statusPublished - Nov 2015

Fingerprint

digestive system diseases
prostaglandins
Prostaglandins
transporters
mutation
Mutation
gene
Genes
genes
small intestine
Small Intestine
protein
RNA splicing
protein depletion
Crohn disease
Exome
RNA Splicing
stop codon
intestinal mucosa
Nonsense Codon

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter. / Umeno, Junji; Hisamatsu, Tadakazu; Esaki, Motohiro; Hirano, Atsushi; Kubokura, Naoya; Asano, Kouichi; Kochi, Shuji; Yanai, Shunichi; Fuyuno, Yuta; Shimamura, Katsuyoshi; Hosoe, Naoki; Ogata, Haruhiko; Watanabe, Takashi; Aoyagi, Kunihiko; Ooi, Hidehisa; Watanabe, Kenji; Yasukawa, Shigeyoshi; Hirai, Fumihito; Matsui, Toshiyuki; Iida, Mitsuo; Yao, Tsuneyoshi; Hibi, Toshifumi; Kosaki, Kenjiro; Kanai, Takanori; Kitazono, Takanari; Matsumoto, Takayuki.

In: PLoS genetics, Vol. 11, No. 11, e1005581, 11.2015.

Research output: Contribution to journalArticle

Umeno, J, Hisamatsu, T, Esaki, M, Hirano, A, Kubokura, N, Asano, K, Kochi, S, Yanai, S, Fuyuno, Y, Shimamura, K, Hosoe, N, Ogata, H, Watanabe, T, Aoyagi, K, Ooi, H, Watanabe, K, Yasukawa, S, Hirai, F, Matsui, T, Iida, M, Yao, T, Hibi, T, Kosaki, K, Kanai, T, Kitazono, T & Matsumoto, T 2015, 'A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter', PLoS genetics, vol. 11, no. 11, e1005581. https://doi.org/10.1371/journal.pgen.1005581
Umeno, Junji ; Hisamatsu, Tadakazu ; Esaki, Motohiro ; Hirano, Atsushi ; Kubokura, Naoya ; Asano, Kouichi ; Kochi, Shuji ; Yanai, Shunichi ; Fuyuno, Yuta ; Shimamura, Katsuyoshi ; Hosoe, Naoki ; Ogata, Haruhiko ; Watanabe, Takashi ; Aoyagi, Kunihiko ; Ooi, Hidehisa ; Watanabe, Kenji ; Yasukawa, Shigeyoshi ; Hirai, Fumihito ; Matsui, Toshiyuki ; Iida, Mitsuo ; Yao, Tsuneyoshi ; Hibi, Toshifumi ; Kosaki, Kenjiro ; Kanai, Takanori ; Kitazono, Takanari ; Matsumoto, Takayuki. / A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter. In: PLoS genetics. 2015 ; Vol. 11, No. 11.
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AU - Umeno, Junji

AU - Hisamatsu, Tadakazu

AU - Esaki, Motohiro

AU - Hirano, Atsushi

AU - Kubokura, Naoya

AU - Asano, Kouichi

AU - Kochi, Shuji

AU - Yanai, Shunichi

AU - Fuyuno, Yuta

AU - Shimamura, Katsuyoshi

AU - Hosoe, Naoki

AU - Ogata, Haruhiko

AU - Watanabe, Takashi

AU - Aoyagi, Kunihiko

AU - Ooi, Hidehisa

AU - Watanabe, Kenji

AU - Yasukawa, Shigeyoshi

AU - Hirai, Fumihito

AU - Matsui, Toshiyuki

AU - Iida, Mitsuo

AU - Yao, Tsuneyoshi

AU - Hibi, Toshifumi

AU - Kosaki, Kenjiro

AU - Kanai, Takanori

AU - Kitazono, Takanari

AU - Matsumoto, Takayuki

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