Mutations in the pH-Sensing G-protein-Coupled Receptor GPR68 Cause Amelogenesis Imperfecta

David A Parry, Claire E L Smith, Walid El-Sayed, James A Poulter, Roger C Shore, Clare V Logan, Chihiro Mogi, Koichi Sato, Fumikazu Okajima, Akihiro Harada, Hong Zhang, Mine Koruyucu, Figen Seymen, Jan C-C Hu, James P Simmer, Mushtaq Ahmed, Hussain Jafri, Colin A Johnson, Chris F Inglehearn, Alan J Mighell

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Amelogenesis is the process of dental enamel formation, leading to the deposition of the hardest tissue in the human body. This process requires the intricate regulation of ion transport and controlled changes to the pH of the developing enamel matrix. The means by which the enamel organ regulates pH during amelogenesis is largely unknown. We identified rare homozygous variants in GPR68 in three families with amelogenesis imperfecta, a genetically and phenotypically heterogeneous group of inherited conditions associated with abnormal enamel formation. Each of these homozygous variants (a large in-frame deletion, a frameshift deletion, and a missense variant) were predicted to result in loss of function. GPR68 encodes a proton-sensing G-protein-coupled receptor with sensitivity in the pH range that occurs in the developing enamel matrix during amelogenesis. Immunohistochemistry of rat mandibles confirmed localization of GPR68 in the enamel organ at all stages of amelogenesis. Our data identify a role for GPR68 as a proton sensor that is required for proper enamel formation.

Original languageEnglish
Pages (from-to)984-990
Number of pages7
JournalAmerican Journal of Human Genetics
Issue number4
Early online date29 Sept 2016
Publication statusPublished - 6 Oct 2016

Keywords / Materials (for Non-textual outputs)

  • Amelogenesis/genetics
  • Amelogenesis Imperfecta/genetics
  • Animals
  • Base Sequence
  • Dental Enamel/growth & development
  • Female
  • Homozygote
  • Humans
  • Hydrogen-Ion Concentration
  • Male
  • Mutation
  • Pedigree
  • Rats
  • Receptors, G-Protein-Coupled/analysis


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