A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter.
A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter.
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DOI：
10.1371/journal.pgen.1005581
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发表时间：
2015-11
期刊：
影响因子：
4.5
通讯作者：
Matsumoto T
中科院分区：
文献类型：
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作者：
Umeno J;Hisamatsu T;Esaki M;Hirano A;Kubokura N;Asano K;Kochi S;Yanai S;Fuyuno Y;Shimamura K;Hosoe N;Ogata H;Watanabe T;Aoyagi K;Ooi H;Watanabe K;Yasukawa S;Hirai F;Matsui T;Iida M;Yao T;Hibi T;Kosaki K;Kanai T;Kitazono T;Matsumoto T
以前，我们提出了一种罕见的常染色体隐性遗传性肠病的特点是持续的血液和蛋白质损失从小肠慢性非特异性多发性溃疡的小肠（CNSU）。通过对5名日本CNSU患者和1名未受影响的个体进行全外显子组测序，我们在SLCO 2A 1基因中发现了4个候选突变，编码前列腺素转运蛋白。分离分析和对照组基因分型数据支持突变的致病性。通过对编码区进行桑格测序，发现12名其他CNSU患者中的11名和603名诊断为克罗恩病的患者中的2名具有纯合或复合杂合SLCO 2A 1突变。总的来说，我们确定了隐性SLCO 2A 1突变位于7个位点。使用RT-PCR，我们证明了所确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，突变SLCO 2A 1蛋白的每个突变表现出受损的前列腺素转运。免疫组化和免疫荧光分析显示，SLCO 2A 1蛋白表达在对照组小肠粘膜血管内皮细胞的细胞膜上，但在受影响的个人中未检测到。这些发现表明，SLCO 2A 1基因编码前列腺素转运蛋白的功能丧失突变导致遗传性肠病CNSU。我们建议一个更合适的命名为“慢性肠病与SLCO 2A 1基因”（CEAS）。胶囊式内窥镜和气囊内窥镜等先进诊断创新使人们更好地了解小肠疾病的内窥镜检查结果。然而，它仍然很难诊断小肠疾病，如克罗恩病，肠结核，非甾体抗炎药引起的肠病的内镜检查结果。我们先前曾报告一种罕见的常染色体隐性遗传性肠病，其特征是持续的血液和蛋白质损失从小肠。这种肠病的临床过程难以控制，免疫抑制治疗无效。在这项研究中，我们确定了隐性突变的SLCO 2A 1基因，编码前列腺素转运蛋白，作为致病变异的这种疾病的外显子组测序的四个家庭，并表明，这种疾病是不同的克罗恩病。我们还表明，在患者中发现的突变导致细胞内前列腺素E2摄取功能障碍。目前的研究结果表明，遗传分析连同详细的临床信息是非常宝贵的疾病的诊断，并可能有一个概念，肠病被称为“胰高血糖素相关肠病”，无论种族背景。
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). 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.