Genetic Variants in Protein Tyrosine Phosphatase Non-Receptor Type 23 Are Responsible for Mesiodens Formation

oleh: Ploy Adisornkanj, Rajit Chanprasit, Steven Eliason, Juan M. Fons, Worrachet Intachai, Sissades Tongsima, Bjorn Olsen, Stefan T. Arold, Chumpol Ngamphiw, Brad A. Amendt, Abigail S. Tucker, Piranit Kantaputra

Format: Article
Diterbitkan: MDPI AG 2023-03-01

Deskripsi

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 <i>PTPN23</i> in seven affected members and six unaffected members. The mode of inheritance was autosomal dominance with incomplete penetrance (53.84%). Two additional mutations in <i>PTPN23</i>, c.2248C>G;p.Pro750Ala and c.3298C>T;p.Arg1100Cys were identified in two unrelated patients with mesiodens. <i>PTPN23</i> 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 <i>PTPN23</i> in oral tissues, while immunofluorescence showed that EGFR was specifically concentrated in the midline epithelium. Importantly, <i>PTPN23</i> mutant protein was shown to have reduced phosphatase activity. In conclusion, mesiodens were associated with genetic variants in <i>PTPN23</i>, suggesting that mesiodens may form due to defects in endosomal trafficking, leading to disrupted midline signaling.