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

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...

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Bibliographic Details
Published in:PLoS genetics 2015-11, Vol.11 (11), p.e1005581-e1005581
Main Authors: 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
Format: Article
Language:English
Subjects:
Analysis
Female
Gene mutations
Genes
Genetic aspects
Genetic Testing
Humans
Immunohistochemistry
Influence
Intestinal Diseases - genetics
Intestinal Diseases - pathology
Intestine, Small - pathology
Male
Mutation
Nonsteroidal anti-inflammatory drugs
Organic Anion Transporters - genetics
Pedigree
Prostaglandins
Small intestine
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Summary: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).
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1005581