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

Takashi Sasaki, Hironori Niizeki, Atsushi Shimizu, Aiko Shiohama, Asami Hirakiyama, Torayuki Okuyama, Atsuhito Seki, Kenji Kabashima, Atsushi Otsuka, Akira Ishiko, Keiji Tanese, Shun Ichi Miyakawa, Jun Ichi Sakabe, Masamitsu Kuwahara, Masayuki Amagai, Hideyuki Okano, Makoto Suematsu, Jun Kudo

Research output: Contribution to journalArticle

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Abstract

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 PDP patients. Follow-up Sanger sequencing showed 5 different SLCO2A1 mutations (c.940+1G>A, p.E427_P430del, p.G104*, p.T347I, 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 a 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.

Original languageEnglish
Pages (from-to)36-44
Number of pages9
JournalJournal of Dermatological Science
Volume68
Issue number1
DOIs
Publication statusPublished - 2012 Oct

Fingerprint

Primary Hypertrophic Osteoarthropathy
Genetic Association Studies
Prostaglandins
Genes
Mutation
15-hydroxyprostaglandin dehydrogenase
Organic Anion Transporters
Gene encoding
DNA
Exome
Dinoprostone
Inborn Genetic Diseases

Keywords

  • CVG
  • Mutation analysis
  • NGS
  • PDP
  • PGT
  • Prostaglandin transporter
  • SLCO2A1
  • SNP
  • Whole exome sequencing

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Molecular Biology

Cite this

Identification of mutations in the prostaglandin transporter gene SLCO2A1 and its phenotype-genotype correlation in Japanese patients with pachydermoperiostosis. / Sasaki, Takashi; Niizeki, Hironori; Shimizu, Atsushi; Shiohama, Aiko; Hirakiyama, Asami; Okuyama, Torayuki; Seki, Atsuhito; Kabashima, Kenji; Otsuka, Atsushi; Ishiko, Akira; Tanese, Keiji; Miyakawa, Shun Ichi; Sakabe, Jun Ichi; Kuwahara, Masamitsu; Amagai, Masayuki; Okano, Hideyuki; Suematsu, Makoto; Kudo, Jun.

In: Journal of Dermatological Science, Vol. 68, No. 1, 10.2012, p. 36-44.

Research output: Contribution to journalArticle

Sasaki, T, Niizeki, H, Shimizu, A, Shiohama, A, Hirakiyama, A, Okuyama, T, Seki, A, Kabashima, K, Otsuka, A, Ishiko, A, Tanese, K, Miyakawa, SI, Sakabe, JI, Kuwahara, M, Amagai, M, Okano, H, Suematsu, M & Kudo, J 2012, 'Identification of mutations in the prostaglandin transporter gene SLCO2A1 and its phenotype-genotype correlation in Japanese patients with pachydermoperiostosis', Journal of Dermatological Science, vol. 68, no. 1, pp. 36-44. https://doi.org/10.1016/j.jdermsci.2012.07.008
Sasaki, Takashi ; Niizeki, Hironori ; Shimizu, Atsushi ; Shiohama, Aiko ; Hirakiyama, Asami ; Okuyama, Torayuki ; Seki, Atsuhito ; Kabashima, Kenji ; Otsuka, Atsushi ; Ishiko, Akira ; Tanese, Keiji ; Miyakawa, Shun Ichi ; Sakabe, Jun Ichi ; Kuwahara, Masamitsu ; Amagai, Masayuki ; Okano, Hideyuki ; Suematsu, Makoto ; Kudo, Jun. / Identification of mutations in the prostaglandin transporter gene SLCO2A1 and its phenotype-genotype correlation in Japanese patients with pachydermoperiostosis. In: Journal of Dermatological Science. 2012 ; Vol. 68, No. 1. pp. 36-44.
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T1 - Identification of mutations in the prostaglandin transporter gene SLCO2A1 and its phenotype-genotype correlation in Japanese patients with pachydermoperiostosis

AU - Sasaki, Takashi

AU - Niizeki, Hironori

AU - Shimizu, Atsushi

AU - Shiohama, Aiko

AU - Hirakiyama, Asami

AU - Okuyama, Torayuki

AU - Seki, Atsuhito

AU - Kabashima, Kenji

AU - Otsuka, Atsushi

AU - Ishiko, Akira

AU - Tanese, Keiji

AU - Miyakawa, Shun Ichi

AU - Sakabe, Jun Ichi

AU - Kuwahara, Masamitsu

AU - Amagai, Masayuki

AU - Okano, Hideyuki

AU - Suematsu, Makoto

AU - Kudo, Jun

PY - 2012/10

Y1 - 2012/10

N2 - 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 PDP patients. Follow-up Sanger sequencing showed 5 different SLCO2A1 mutations (c.940+1G>A, p.E427_P430del, p.G104*, p.T347I, 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 a 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.

AB - 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 PDP patients. Follow-up Sanger sequencing showed 5 different SLCO2A1 mutations (c.940+1G>A, p.E427_P430del, p.G104*, p.T347I, 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 a 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.

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