TY - JOUR
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 - Kudoh, Jun
N1 - Funding Information:
We thank the patients and their families for their generous cooperation. We also thank Dr. R. Horikawa, Dr. S. Tanaka, and Dr. N. Tanaka for referring patients; Dr. H. Saya and Dr. G. Yoshida for critical reading of the manuscript; and Ms. M. Furuhashi, Ms. I. Koya, and Core Instrumentation Facility, Keio University School of Medicine for their excellent technical assistance. This work was supported in part by a grant from the Ministry of Health, Labour and Welfare (Research for Intractable Diseases) (to H.N.); the Global COE Program (for Education and Research Center for Stem Cell Medicine, to H.O.) (for In vivo Human Metabolomic Systems Biology, to M.S.), Project for the Realization of Regenerative Medicine and Support (for the Core Institutes for iPS cell research, to H.O.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) ; and a Grant-in-Aid for Scientific Research on Innovative Areas ( 23129505 ) (to J.K.) from MEXT.
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.
KW - CVG
KW - Mutation analysis
KW - NGS
KW - PDP
KW - PGT
KW - Prostaglandin transporter
KW - SLCO2A1
KW - SNP
KW - Whole exome sequencing
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U2 - 10.1016/j.jdermsci.2012.07.008
DO - 10.1016/j.jdermsci.2012.07.008
M3 - Article
C2 - 22906430
AN - SCOPUS:84865771808
VL - 68
SP - 36
EP - 44
JO - Journal of Dermatological Science
JF - Journal of Dermatological Science
SN - 0923-1811
IS - 1
ER -