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

Abstract
A mesiodens is a supernumerary tooth located in the midline of the premaxilla. In order to investigate the genetic etiology of mesiodens, clinical and radiographic examination and whole exome sequencing (WES) were performed in 24 family members of a two-generation Hmong family and additionally in 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.

Citation
Adisornkanj, P., Chanprasit, R., Eliason, S., Fons, J. M., Intachai, W., Tongsima, S., Olsen, B., Arold, S. T., Ngamphiw, C., Amendt, B. A., Tucker, A. S., & Kantaputra, P. (2023). Genetic Variants in Protein Tyrosine Phosphatase Non-Receptor Type 23 Are Responsible for Mesiodens Formation. Biology, 12(3), 393. https://doi.org/10.3390/biology12030393

Acknowledgements
This work was supported by the Genomics Thailand Research Grant of Health Systems Research Institute (Grant no. 64-123), the King Abdullah University of Science and Technology (KAUST) through the baseline fund and the Award No. FCC/1/1976-25 and REI/1/4446-01 from the Office of Sponsored Research (OSR). We thank our patients and their families for their kind cooperation and for allowing us to use their medical and dental information for the benefit of other patients.

Publisher
MDPI AG

Journal
Biology

DOI
10.3390/biology12030393

Additional Links
https://www.mdpi.com/2079-7737/12/3/393

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