Three novel mutations in the SLCO2A1 gene in two Chinese families with primary hypertrophic osteoarthropathy

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Primary hypertrophic osteoarthropathy (PHO (MIM 167100)) is a rare genetic disease characterized by pachyderma, periostosis and digital clubbing. Mutations in the 15-hydroxy-prostaglandin dehydrogenase (HPGD) gene and solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene have been demonstrated to be pathogenic causes. We aimed to identify the genetic cause of 2 unrelated patients with PHO. Urinary levels of prostaglandin E2 and prostaglandin E metabolite were measured in Proband 1 and his sister by competitive ELISAs. Mutation analysis of the HPGD and SLCO2A1 genes were conducted on both probands with PHO. Genomic DNAs of 100 healthy controls were isolated and subjected to polymerase chain reaction and direct DNA sequencing. The identified mutations were further confirmed in the parents of Proband 1. Protein modeling and data from PolyPhen-2 were used to evaluate the effects of novel missense mutations on protein SLCO2A1. The urinary levels of prostaglandin E2 and prostaglandin E metabolite in Proband 1 were much higher than those in unaffected individuals. Molecular genetic analysis revealed four SLCO2A1 mutations, including 3 novel ones (p.Arg603X, p.Gly183Arg and p.Asn534Lys) and a founder mutation, c.940+1G>A, in two probands with PHO. Missense mutations p.Gly183Arg and p.Asn534Lys, at highly conserved positions, were both predicted to be damaging. Protein modeling indicated that the mutation p.Gly183Arg altered the 3-dimensional structure of SLCO2A1. Three novel mutations within the SLCO2A1 gene have been demonstrated to be associated with Chinese PHO patients.