Umeno Junji, Hisamatsu Tadakazu, Esaki Motohiro, Hirano Atsushi, Kubokura Naoya, Asano Kouichi, Kochi Shuji, Yanai Shunichi, Fuyuno Yuta, Shimamura Katsuyoshi, Hosoe Naoki, Ogata Haruhiko, Watanabe Takashi, Aoyagi Kunihiko, Ooi Hidehisa, Watanabe Kenji, Yasukawa Shigeyoshi, Hirai Fumihito, Matsui Toshiyuki, Iida Mitsuo, Yao Tsuneyoshi, Hibi Toshifumi, Kosaki Kenjiro, Kanai Takanori, Kitazono Takanari, Matsumoto Takayuki
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
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).
此前，我们提出了一种罕见的常染色体隐性遗传性肠病，其特征为小肠持续性失血和蛋白质丢失，表现为小肠慢性非特异性多发性溃疡（CNSU）。通过对5例CNSU日本患者和1例未受影响个体进行全外显子组测序，我们在编码前列腺素转运体的SLCO2A1基因中发现了4个候选突变。突变的致病性得到了对照中的家系分析和基因分型数据的支持。通过对编码区进行桑格测序，发现12例其他CNSU患者中有11例以及603例诊断为克罗恩病的患者中有2例存在纯合或复合杂合的SLCO2A1突变。我们总共在7个位点鉴定出隐性SLCO2A1突变。使用逆转录聚合酶链反应（RT-PCR），我们证明所鉴定的剪接位点突变改变了RNA剪接，并引入了提前终止密码子。示踪前列腺素E2摄取分析表明，每个突变的突变型SLCO2A1蛋白均表现出前列腺素转运受损。免疫组织化学和免疫荧光分析显示，对照受试者小肠黏膜血管内皮细胞的细胞膜上表达有SLCO2A1蛋白，但在受影响个体中未检测到。这些发现表明，编码前列腺素转运体的SLCO2A1基因功能丧失性突变导致遗传性肠病CNSU。我们建议使用更合适的命名“与SLCO2A1基因相关的慢性肠病”（CEAS）。
