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

Authors :
Junji Umeno
Tadakazu Hisamatsu
Motohiro Esaki
Atsushi Hirano
Naoya Kubokura
Kouichi Asano
Shuji Kochi
Shunichi Yanai
Yuta Fuyuno
Katsuyoshi Shimamura
Naoki Hosoe
Haruhiko Ogata
Takashi Watanabe
Kunihiko Aoyagi
Hidehisa Ooi
Kenji Watanabe
Shigeyoshi Yasukawa
Fumihito Hirai
Toshiyuki Matsui
Mitsuo Iida
Tsuneyoshi Yao
Toshifumi Hibi
Kenjiro Kosaki
Takanori Kanai
Takanari Kitazono
Takayuki Matsumoto
Source :
PLoS Genetics, Vol 11, Iss 11, p e1005581 (2015)
Publication Year :
2015
Publisher :
Public Library of Science (PLoS), 2015.

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).

Subjects

Subjects :
Genetics
QH426-470

Details

Language :
English
ISSN :
15537390 and 15537404
Volume :
11
Issue :
11
Database :
Directory of Open Access Journals
Journal :
PLoS Genetics
Publication Type :
Academic Journal
Accession number :
edsdoj.56351e6fd37749f2ac019d31e6d6b04f
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pgen.1005581