Identification of mutations in the prostaglandin transporter gene SLCO2A1 and its phenotype-genotype correlation in Japanese patients with pachydermoperiostosis

被引：63

作者：

Sasaki, Takashi ^{[2
,3
]}

Niizeki, Hironori ^{[1
]}

Shimizu, Atsushi ^{[4
]}

Shiohama, Aiko ^{[5
]}

Hirakiyama, Asami ^{[1
,6
]}

Okuyama, Torayuki ^{[6
]}

Seki, Atsuhito ^{[7
]}

Kabashima, Kenji ^{[8
]}

Otsuka, Atsushi ^{[8
]}

Ishiko, Akira ^{[9
]}

Tanese, Keiji ^{[10
]}

Miyakawa, Shun-ichi ^{[10
]}

Sakabe, Jun-ichi ^{[11
]}

Kuwahara, Masamitsu ^{[12
]}

Amagai, Masayuki ^{[3
]}

Okano, Hideyuki ^{[13
]}

Suematsu, Makoto ^{[14
]}

Kudoh, Jun ^{[5
]}

机构：

[1] Natl Ctr Child Hlth & Dev, Dept Dermatol, Setagaya Ku, Tokyo 1578535, Japan

[2] Keio Univ, Sch Med, Ctr Integrated Med Res, Shinjuku Ku, Tokyo, Japan

[3] Keio Univ, Sch Med, Dept Dermatol, Shinjuku Ku, Tokyo, Japan

[4] Keio Univ, Sch Med, Dept Mol Biol, Shinjuku Ku, Tokyo, Japan

[5] Keio Univ, Sch Med, Lab Gene Med, Shinjuku Ku, Tokyo, Japan

[6] Natl Ctr Child Hlth & Dev, Dept Lab Med, Setagaya Ku, Tokyo 1578535, Japan

[7] Natl Ctr Child Hlth & Dev, Dept Orthoped, Setagaya Ku, Tokyo 1578535, Japan

[8] Kyoto Univ, Grad Sch Med, Dept Dermatol, Kyoto, Japan

[9] Toho Univ, Sch Med, Dept Dermatol 1, Ota Ku, Tokyo, Japan

[10] Kawasaki Municipal Hosp, Div Dermatol, Kawasaki, Kanagawa, Japan

[11] Hamamatsu Univ Sch Med, Dept Dermatol, Hamamatsu, Shizuoka 4312102, Japan

[12] Nara Med Univ, Div Plast Surg, Kashihara, Nara 634, Japan

[13] Keio Univ, Sch Med, Dept Physiol, Shinjuku Ku, Tokyo, Japan

[14] Keio Univ, Sch Med, Dept Biochem, Shinjuku Ku, Tokyo, Japan

来源：

JOURNAL OF DERMATOLOGICAL SCIENCE | 2012年 / 68卷 / 01期

关键词：

PDP; Whole exome sequencing; Mutation analysis; SLCO2A1; Prostaglandin transporter; PRIMARY HYPERTROPHIC OSTEOARTHROPATHY; HPGD MUTATIONS;

D O I：

10.1016/j.jdermsci.2012.07.008

中图分类号：

R75 [皮肤病学与性病学];

学科分类号：

100206 ;

摘要：

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.

引用

页码：36 / 44

页数：9

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