Mutations in the pH-Sensing G-protein-Coupled Receptor GPR68 Cause Amelogenesis Imperfecta.
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.
Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
David A
DA
Parry
Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.
Claire E L
CE
Smith
Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK; School of Dentistry, Department of Oral Biology, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK; Oral Biology Department, College of Dentistry, Suez Canal University, El Salam District, Ismaileya 41611, Egypt; Oral Biology Department, College of Dentistry, Gulf Medical University, Al Jurf, Ajman 3787, United Arab Emirates.
Walid
W
El-Sayed
Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.
James A
JA
Poulter
School of Dentistry, Department of Oral Biology, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
Roger C
RC
Shore
Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.
Clare V
CV
Logan
Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
Chihiro
C
Mogi
Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
Koichi
K
Sato
Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
Fumikazu
F
Okajima
Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Akihiro
A
Harada
Departments of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1210 Eisenhower Place, Ann Arbor, MI 48108, USA.
Hong
H
Zhang
Department of Pedodontics, Faculty of Dentistry, Istanbul University, Istanbul 34116, Turkey.
Mine
M
Koruyucu
Department of Pedodontics, Faculty of Dentistry, Istanbul University, Istanbul 34116, Turkey.
Figen
F
Seymen
Departments of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1210 Eisenhower Place, Ann Arbor, MI 48108, USA.
Jan C-C
JC
Hu
Departments of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1210 Eisenhower Place, Ann Arbor, MI 48108, USA.
James P
JP
Simmer
Clinical Genetics, Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital, Leeds LS7 4SA, UK.
Mushtaq
M
Ahmed
Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK; Gene Tech Lab 146/1, Shadman Jail Road, Lahore 54000, Pakistan.
Hussain
H
Jafri
Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.
Colin A
CA
Johnson
Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.
Chris F
CF
Inglehearn
Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK; School of Dentistry, Department of Oral Biology, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK. Electronic address: a.j.mighell@leeds.ac.uk.
Alan J
AJ
Mighell
D000566:Amelogenesis / Q000235:genetics; D000567:Amelogenesis Imperfecta / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D003743:Dental Enamel / Q000254:growth & development / Q000473:pathology; D005260:Female; D006720:Homozygote; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D009154:Mutation; D010375:Pedigree; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000235:genetics*
C486281:GPR68 protein, human; C000619305:GPR68 protein, rat; D043562:Receptors, G-Protein-Coupled
Amelogenesis imperfecta; GPR68; amelogenesis; pH sensing; teeth
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