title: 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).
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Umeno
authors.affiliation: 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.
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Hisamatsu
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Esaki
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirano
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Kubokura
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Asano
authors.affiliation: Department of Gastroenterology, Matsuyama Red Cross Hospital, Matsuyama, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kochi
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Yanai
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Fuyuno
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Shimamura
authors.affiliation: Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hosoe
authors.affiliation: Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Ogata
authors.affiliation: Department of Gastroenterology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Gastroenterology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Aoyagi
authors.affiliation: Division of Gastroenterology, Imamura Hospital, Kagoshima, Japan.
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Ooi
authors.affiliation: Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino, Japan.
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Yasukawa
authors.affiliation: Department of Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino, Japan.
authors.forename: Fumihito
authors.initials: F
authors.lastname: Hirai
authors.affiliation: Department of Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.|Kyushu Central Hospital, Fukuoka, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Iida
authors.affiliation: Department of Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino, Japan.|Sada Hospital, Fukuoka, Japan.
authors.forename: Tsuneyoshi
authors.initials: T
authors.lastname: Yao
authors.affiliation: Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
authors.affiliation: Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kosaki
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takanari
authors.initials: T
authors.lastname: Kitazono
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.|Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Iwate Medical University, Morioka, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D005260:Female; D005820:Genetic Testing; D006801:Humans; D007410:Intestinal Diseases / Q000235:genetics* / Q000473:pathology; D007421:Intestine, Small / Q000473:pathology*; D008297:Male; D009154:Mutation; D027361:Organic Anion Transporters / Q000235:genetics*; D010375:Pedigree
chemical_list: D027361:Organic Anion Transporters; C503526:SLCO2A1 protein, human