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


CONCLUSIONS
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.
Center for Integrated Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Takashi
T
Sasaki
Hironori
H
Niizeki
Atsushi
A
Shimizu
Aiko
A
Shiohama
Asami
A
Hirakiyama
Torayuki
T
Okuyama
Atsuhito
A
Seki
Kenji
K
Kabashima
Atsushi
A
Otsuka
Akira
A
Ishiko
Keiji
K
Tanese
Shun-ichi
S
Miyakawa
Jun-ichi
J
Sakabe
Masamitsu
M
Kuwahara
Masayuki
M
Amagai
Hideyuki
H
Okano
Makoto
M
Suematsu
Jun
J
Kudoh
D000328:Adult; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D004252:DNA Mutational Analysis; D015232:Dinoprostone / Q000097:blood / Q000378:metabolism* / Q000652:urine; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D010004:Osteoarthropathy, Primary Hypertrophic / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012720:Severity of Illness Index; D055815:Young Adult
D027361:Organic Anion Transporters; C503526:SLCO2A1 protein, human; D015232:Dinoprostone