Parry David A, Smith Claire E L, El-Sayed Walid, Poulter James A, Shore Roger C, Logan Clare V, Mogi Chihiro, Sato Koichi, Okajima Fumikazu, Harada Akihiro, Zhang Hong, Koruyucu Mine, Seymen Figen, Hu Jan C-C, Simmer James P, Ahmed Mushtaq, Jafri Hussain, Johnson Colin A, Inglehearn Chris F, Mighell Alan J
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.
Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.
Am J Hum Genet. 2016 Oct 6;99(4):984-990. doi: 10.1016/j.ajhg.2016.08.020. Epub 2016 Sep 29.
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.
釉质形成是牙釉质形成的过程，会导致人体中最坚硬的组织沉积。这个过程需要对离子转运进行复杂的调节，并对正在发育的釉质基质的pH值进行可控的改变。在釉质形成过程中，釉器调节pH值的方式在很大程度上尚不清楚。我们在三个患有牙釉质发育不全的家族中鉴定出了GPR68中的罕见纯合变体，牙釉质发育不全是一组遗传和表型异质性的遗传性疾病，与釉质形成异常有关。这些纯合变体中的每一个（一个大的框内缺失、一个移码缺失和一个错义变体）预计都会导致功能丧失。GPR68编码一种质子感应G蛋白偶联受体，在釉质形成过程中对正在发育的釉质基质中出现的pH范围敏感。大鼠下颌骨的免疫组织化学证实了GPR68在釉质形成各阶段的釉器中的定位。我们的数据确定了GPR68作为质子传感器在正常釉质形成中所起的作用。
