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).
Highlights
The use of capsule endoscopy and balloon endoscopy has provided a better understanding of the features of small bowel ulcers among various gastrointestinal disorders, such as Crohn’s disease (CD), intestinal tuberculosis, and nonsteroidal anti-inflammatory drug (NSAID)– induced enteropathy [1,2]
We previously reported a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine
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
Summary
The use of capsule endoscopy and balloon endoscopy has provided a better understanding of the features of small bowel ulcers among various gastrointestinal disorders, such as Crohn’s disease (CD), intestinal tuberculosis, and nonsteroidal anti-inflammatory drug (NSAID)– induced enteropathy [1,2]. The macroscopic findings of CNSU are characterized by multiple thin ulcers in a linear or circumferential configuration and concentric stenosis, and apparently mimic those of NSAIDinduced enteropathy [4,5,6,7]. CNSU predominantly occurs in females and the symptoms, such as general fatigue, edema, and abdominal pain, appear during adolescence. CNSU predominantly occurs in females, it appears to be an autosomal recessive inherited disorder because of frequent parental consanguinity [8]. We replicated our findings in other patients with CNSU and established a genetic cause for this inherited disease
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