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

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).

Author Summary

Advanced diagnostic innovations such as capsule endoscopy and balloon endoscopy have provided better understanding of endoscopic findings of small bowel diseases. However, it remains difficult to diagnose small intestinal diseases such as Crohn’s disease, intestinal tuberculosis, and nonsteroidal anti-inflammatory drug-induced enteropathy by the endoscopic findings alone. We previously reported a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine. This enteropathy has an intractable clinical course with ineffectiveness of immunosuppressive treatment. In this study, we identified recessive mutations in the SLCO2A1 gene, encoding a prostaglandin transporter, as causative variants of this disorder by exome sequencing of four families, and showed that this disease is distinct from Crohn’s disease. We also showed that the mutations found in the patients caused functional impairment of prostaglandin E2 uptake within cells. The present findings suggest that genetic analysis together with detailed clinical information is invaluable for diagnosis of the disease, and that there may be a concept of enteropathy referred to as “prostaglandin-associated enteropathy”, irrespective of ethnic background.