David A. Parry, Claire E. L. Smith, Walid El-Sayed, James A

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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 The American Journal of Human Genetics Volume 99, Issue 4, Pages 984-990 (October 2016) DOI: 10.1016/j.ajhg.2016.08.020 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Clinical Appearances of the Dentition in Individuals with GPR68 Mutations The clinical phenotype is consistent with hypomaturation AI. (A) The lower arch permanent dentition of the proband at 15 years old is characterized by opaque, discolored enamel that in part is due to extrinsic staining. The upper dentition has been restored. The marked anterior open bite was not observed in other affected family members. (B) An intraoral radiograph of the proband at 14 years old illustrates a near-normal enamel morphology in the recently erupted second premolar tooth (arrow with asterisk) but premature failure of enamel with tooth substance loss in the permanent molar teeth (arrows), which have been present in the mouth longer and have been subject to the greatest functional load. A crowned upper tooth is marked with a cross. (C) The dentition of an affected sibling at 20 years old is characterized by less-extrinsic staining but clear attrition along the occlusal plane and failure of posterior teeth, several of which are missing. (D) Comparative occlusal views of the lower right quadrants in the proband (i) and sibling (ii) confirm the similarities in enamel appearances and the more-extensive attrition in the older individual, whose anterior teeth occlude. Restorations are marked with arrows, and a grossly broken-down tooth is marked with an asterisk. The American Journal of Human Genetics 2016 99, 984-990DOI: (10.1016/j.ajhg.2016.08.020) Copyright © 2016 The Authors Terms and Conditions

Figure 2 Identification of a GPR68 Deletion in Family AI-5 (A) Segregation of a deletion in GPR68 with amelogenesis imperfecta in family AI-5. The coding sequence of GPR68 was amplified by PCR to produce a 1,685 bp product in control DNA (Con). All affected AI-5 family members for whom DNA was available were homozygous for a 450 bp deletion, whereas unaffected carriers were heterozygous for this deletion. Neg; negative control. (B) Electropherograms of GPR68 genomic DNA sequence showing the homozygous c.386_835del (GenBank: NM_001177676.1) deletion in an affected individual, the same mutation in a heterozygous state in a carrier, and normal sequence from control DNA. The American Journal of Human Genetics 2016 99, 984-990DOI: (10.1016/j.ajhg.2016.08.020) Copyright © 2016 The Authors Terms and Conditions

Figure 3 Identification of GPR68 Mutations in Two Additional Families Affected by Amelogenesis Imperfecta (A and B) Pedigrees of family AI-178 (A) and family TKTO (B). Dots indicate family members for whom DNA samples were available. (C) IGV snapshot of the frameshift mutation identified in family AI-178. (D) Sanger traces of the missense mutation identified in family TKTO. (E) Schematic depiction of the GPR68 transcript and encoded protein features. UTR regions are shown in thin gray boxes, introns are indicated by dashed lines, and the coding region is shown by a taller white box. Light green regions indicate transmembrane helices, and purple ovals denote histidine residues shown to be essential for the normal pH-sensing function or structural integrity of GPR68.16 Variants identified in this study are marked in red with the associated protein consequences. The American Journal of Human Genetics 2016 99, 984-990DOI: (10.1016/j.ajhg.2016.08.020) Copyright © 2016 The Authors Terms and Conditions

Figure 4 GPR68 localization during Rat Incisor Development Use of a previously characterized antibody25,29 (Lifespan Biosciences, LS-A1194) allowed observation of GPR68 immunoreactivity in the enamel organ throughout amelogenesis. Staining is visible in the stellate reticulum (open arrow head) and ameloblasts (arrow) at the secretary stage. The panel inset shows a negative control where the primary antibody has been omitted. The scale bar represents 100 μm. The American Journal of Human Genetics 2016 99, 984-990DOI: (10.1016/j.ajhg.2016.08.020) Copyright © 2016 The Authors Terms and Conditions