Identification of mutations in the prostaglandin transporter gene SLCO2A1 and its phenotype-genotype correlation in Japanese patients with pachydermoperiostosis
Identification of mutations in the prostaglandin transporter gene SLCO2A1 and its phenotype-genotype correlation in Japanese patients with pachydermoperiostosis
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DOI：
10.1016/j.jdermsci.2012.07.008
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发表时间：
2012-10-01
影响因子：
4.6
通讯作者：
Kudoh, Jun
中科院分区：
文献类型：
--
作者：
Sasaki, Takashi;Niizeki, Hironori;Kudoh, Jun
背景：厚皮骨膜病（PDP）是一种罕见的遗传性疾病，以3个主要症状为特征：厚皮病包括垂直性旋转性皮肤（CVG）、骨膜病和手指杵状症。最近，编码15-羟基前列腺素脱氢酶（15-PGDH）的基因HPGD的纯合突变被发现与PDP有关。然而，在日本PDP患者中尚未发现HPGD突变。目的：利用下一代DNA测序仪（NGS）对PDP进行全外显子组测序，鉴定PDP的新致病基因。方法：纳入5例患者，包括2例患者-家长三人组。通过NGS对整个编码区进行测序，以确定与PDP相关的候选突变。候选突变随后使用Sanger方法测序。为了确定临床特征，我们分析了5例PDP患者和另外1例特发性CVG患者的组织学样本、血清和尿前列腺素E2 （PGE2）水平。结果：通过对全外显子组测序数据的初步分析，我们在3例POP患者中发现了编码前列腺素转运蛋白的溶质载体有机阴离子转运蛋白家族成员2A1 （SLCO2A1）基因的突变。Sanger测序结果显示，4例无亲缘关系PDP患者中存在5种不同的SLCO2A1突变（c.940+1G > A, p.E427_P430del, p.G104*, p.T3471, p.p q556h）。此外，在4例PDP患者中发现的3例剪接位点突变c.940+1G > A被确定为日本人群中的始创突变。此外，PDP患者中这些SLCO2A1突变的组合也可能与疾病严重程度相关。结论：我们发现SLCO2A1是一个与PDP有关的新基因。虽然SLCO2A1基因只是发现的第二个与PDP相关的基因，但它很可能是日本人群中PDP的主要原因。(c) 2012年日本皮肤病调查学会。爱思唯尔爱尔兰有限公司出版。版权所有。
Background: Pachydermoperiostosis (PDP) is a rare genetic disorder characterized by 3 major symptoms: pachydermia including cutis verticis gyrata (CVG), periostosis, and finger clubbing. Recently, a homozygous mutation in the gene HPGD, which encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH), was found to be associated with PDP. However, mutations in HPGD have not been identified in Japanese PDP patients.Objective: We aimed to identify a novel responsible gene for PDP using whole exome sequencing by next-generation DNA sequencer (NGS).Methods: Five patients, including 2 patient-parent trios were enrolled in this study. Entire coding regions were sequenced by NGS to identify candidate mutations associated with PDP. The candidate mutations were subsequently sequenced using the Sanger method. To determine clinical characteristics, we analyzed histological samples, as well as serum and urinary prostaglandin E2 (PGE2) levels for each of the 5 PDP patients, and 1 additional patient with idiopathic CVG.Results: From initial analyses of whole exome sequencing data, we identified mutations in the solute carrier organic anion transporter family, member 2A1 (SLCO2A1) gene, encoding prostaglandin transporter, in 3 of the POP patients. Follow-up Sanger sequencing showed 5 different SLCO2A1 mutations (c.940+1G > A, p.E427_P430del, p.G104*, p.T3471, p.Q556H) in 4 unrelated PDP patients. In addition, the splice-site mutation c.940+1G > A identified in 3 of 4 PDP patients was determined to be founder mutation in the Japanese population. Furthermore, it is likely that the combination of these SLCO2A1 mutations in PDP patients is also associated with disease severity.Conclusion: We found that SLCO2A1 is a novel gene responsible for PDP. Although the SLCO2A1 gene is only the second gene discovered to be associated with PDP, it is likely to be a major cause of PDP in the Japanese population. (c) 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.