Department of Anatomy and Cell Biology and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA
Juan M. Fons
Centre for Craniofacial and Regenerative Biology, King’s College London, Floor 27 Guy’ Hospital, London Bridge, London SE1 9RT, UK
Worrachet Intachai
Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
Sissades Tongsima
National Biobank of Thailand, National Science and Technology Development Agency, Thailand Science Park, Pathum Thani 12120, Thailand
Bjorn Olsen
Department of Developmental Biology, Harvard School of Dental Medicine, Harvard University, Boston, MA 02115, USA
Stefan T. Arold
Computational Bioscience Research Center, Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia
Chumpol Ngamphiw
National Biobank of Thailand, National Science and Technology Development Agency, Thailand Science Park, Pathum Thani 12120, Thailand
Brad A. Amendt
Department of Anatomy and Cell Biology and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA
Abigail S. Tucker
Centre for Craniofacial and Regenerative Biology, King’s College London, Floor 27 Guy’ Hospital, London Bridge, London SE1 9RT, UK
Piranit Kantaputra
Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
A mesiodens is a supernumerary tooth located in the midline of the premaxilla. To investigate the genetic cause of mesiodens, clinical and radiographic examination were performed on 23 family members of a two-generation Hmong family. Whole exome sequencing (WES) or Sanger sequencing were performed in 22 family members and two unrelated Thai patients with mesiodens. WES in the Hmong family revealed a missense mutation (c.1807G>A;p.Glu603Lys) in PTPN23 in seven affected members and six unaffected members. The mode of inheritance was autosomal dominance with incomplete penetrance (53.84%). Two additional mutations in PTPN23, c.2248C>G;p.Pro750Ala and c.3298C>T;p.Arg1100Cys were identified in two unrelated patients with mesiodens. PTPN23 is a regulator of endosomal trafficking functioning to move activated membrane receptors, such as EGFR, from the endosomal sorting complex towards the ESCRT-III complex for multivesicular body biogenesis, lysosomal degradation, and subsequent downregulation of receptor signaling. Immunohistochemical study and RNAscope on developing mouse embryos showed broad expression of PTPN23 in oral tissues, while immunofluorescence showed that EGFR was specifically concentrated in the midline epithelium. Importantly, PTPN23 mutant protein was shown to have reduced phosphatase activity. In conclusion, mesiodens were associated with genetic variants in PTPN23, suggesting that mesiodens may form due to defects in endosomal trafficking, leading to disrupted midline signaling.
