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PLoS Genet. 2015 Nov 5;11(11):e1005581. doi: 10.1371/journal.pgen.1005581. eCollection 2015 Nov.

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

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Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
The Third Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Japan.
Department of Gastroenterology, Matsuyama Red Cross Hospital, Matsuyama, Japan.
Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Tokyo, Japan.
Department of Gastroenterology, Fukuoka University School of Medicine, Fukuoka, Japan.
Division of Gastroenterology, Imamura Hospital, Kagoshima, Japan.
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Department of Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino, Japan.
Kyushu Central Hospital, Fukuoka, Japan.
Sada Hospital, Fukuoka, Japan.
Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Iwate Medical University, Morioka, Japan.


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).

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