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

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


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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • Genetic Testing
  • Humans
  • Intestinal Diseases / genetics*
  • Intestinal Diseases / pathology
  • Intestine, Small / pathology*
  • Male
  • Mutation*
  • Organic Anion Transporters / genetics*
  • Pedigree


  • Organic Anion Transporters
  • SLCO2A1 protein, human

Grants and funding

This work was supported by the Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and Development, (AMED) (15ek0109053h0002 to Dr. Matsumoto) and by grants from the Japan Society for the Promotion of Science (JSPS) KAKENHI (25460953, to Drs. Umeno, Esaki, and Matsumoto; 15H04811, to Dr. Hisamatsu), the Japanese Ministry of Education, Culture, Sports, Science and Technology (to Dr. Hisamatsu), the Japanese Ministry of Health, Labour and Welfare (to Dr. Hisamatsu and Mr. Shimamura), the Keio University Medical Fund (to Dr. Hisamatsu), and the Kaibara Morikazu Medical Science Promotion Foundation (to Dr. Umeno). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.