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

dc.contributor.authorAdisornkanj, Ploy
dc.contributor.authorChanprasit, Rajit
dc.contributor.authorEliason, Steven
dc.contributor.authorFons, Juan M.
dc.contributor.authorIntachai, Worrachet
dc.contributor.authorTongsima, Sissades
dc.contributor.authorOlsen, Bjorn
dc.contributor.authorArold, Stefan T.
dc.contributor.authorNgamphiw, Chumpol
dc.contributor.authorAmendt, Brad A.
dc.contributor.authorTucker, Abigail S.
dc.contributor.authorKantaputra, Piranit
dc.contributor.departmentComputational Bioscience Research Center, Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia
dc.contributor.departmentBioscience Program
dc.contributor.departmentComputational Bioscience Research Center (CBRC)
dc.contributor.departmentBiological and Environmental Science and Engineering (BESE) Division
dc.contributor.departmentEnvironmental Science and Engineering Program
dc.contributor.institutionCenter of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
dc.contributor.institutionDivision of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
dc.contributor.institutionDental Department, Wiang Kaen Hospital, Wiang Kaen, Chiang Rai 57310, Thailand
dc.contributor.institutionDepartment of Anatomy and Cell Biology and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA
dc.contributor.institutionCentre for Craniofacial and Regenerative Biology, King’s College London, Floor 27 Guy’ Hospital, London Bridge, London SE1 9RT, UK
dc.contributor.institutionNational Biobank of Thailand, National Science and Technology Development Agency, Thailand Science Park, Pathum Thani 12120, Thailand
dc.contributor.institutionDepartment of Developmental Biology, Harvard School of Dental Medicine, Harvard University, Boston, MA 02115, USA
dc.contributor.institutionCenter for Structural Biology, National Institute of Health and Medical Research, National Centre for Scientific Research, University of Montpellier, 34090 Montpellier, France
dc.contributor.institutionIowa Institute of Oral Health Research, University of Iowa, Iowa City, IA 52242, USA
dc.date.accepted2023-02-28
dc.date.accessioned2023-03-05T09:56:21Z
dc.date.available2023-03-05T09:56:21Z
dc.date.issued2023-03-01
dc.description.abstractA 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.
dc.description.sponsorshipThis 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.
dc.eprint.versionPublisher's Version/PDF
dc.identifier.citationAdisornkanj, 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
dc.identifier.doi10.3390/biology12030393
dc.identifier.issn2079-7737
dc.identifier.issue3
dc.identifier.journalBiology
dc.identifier.pages393
dc.identifier.urihttp://hdl.handle.net/10754/689986
dc.identifier.volume12
dc.publisherMDPI AG
dc.relation.urlhttps://www.mdpi.com/2079-7737/12/3/393
dc.rightsArchived with thanks to Biology under a Creative Commons license, details at: https://creativecommons.org/licenses/by/4.0/
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleGenetic Variants in Protein Tyrosine Phosphatase Non-Receptor Type 23 Are Responsible for Mesiodens Formation
dc.typeArticle
display.details.left<span><h5>License</h5>https://creativecommons.org/licenses/by/4.0/<br><br><h5>Type</h5>Article<br><br><h5>Authors</h5><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0002-8096-8809&spc.sf=dc.date.issued&spc.sd=DESC">Adisornkanj, Ploy</a> <a href="https://orcid.org/0000-0002-8096-8809" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Chanprasit, Rajit,equals">Chanprasit, Rajit</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Eliason, Steven,equals">Eliason, Steven</a><br><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0002-6044-1989&spc.sf=dc.date.issued&spc.sd=DESC">Fons, Juan M.</a> <a href="https://orcid.org/0000-0002-6044-1989" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Intachai, Worrachet,equals">Intachai, Worrachet</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Tongsima, Sissades,equals">Tongsima, Sissades</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Olsen, Bjorn,equals">Olsen, Bjorn</a><br><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0001-5278-0668&spc.sf=dc.date.issued&spc.sd=DESC">Arold, Stefan T.</a> <a href="https://orcid.org/0000-0001-5278-0668" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0002-8581-397X&spc.sf=dc.date.issued&spc.sd=DESC">Ngamphiw, Chumpol</a> <a href="https://orcid.org/0000-0002-8581-397X" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Amendt, Brad A.,equals">Amendt, Brad A.</a><br><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0001-8871-6094&spc.sf=dc.date.issued&spc.sd=DESC">Tucker, Abigail S.</a> <a href="https://orcid.org/0000-0001-8871-6094" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0001-9841-0881&spc.sf=dc.date.issued&spc.sd=DESC">Kantaputra, Piranit</a> <a href="https://orcid.org/0000-0001-9841-0881" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><br><h5>KAUST Department</h5><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Computational Bioscience Research Center, Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia,equals">Computational Bioscience Research Center, Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Bioscience Program,equals">Bioscience Program</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Computational Bioscience Research Center (CBRC),equals">Computational Bioscience Research Center (CBRC)</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Biological and Environmental Science and Engineering (BESE) Division,equals">Biological and Environmental Science and Engineering (BESE) Division</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Environmental Science and Engineering Program,equals">Environmental Science and Engineering Program</a><br><br><h5>KAUST Grant Number</h5>FCC/1/1976-25<br>REI/1/4446-01<br><br><h5>Date</h5>2023-03-01</span>
display.details.right<span><h5>Abstract</h5>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.<br><br><h5>Citation</h5>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<br><br><h5>Acknowledgements</h5>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.<br><br><h5>Publisher</h5><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.publisher=MDPI AG,equals">MDPI AG</a><br><br><h5>Journal</h5><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.journal=Biology,equals">Biology</a><br><br><h5>DOI</h5><a href="https://doi.org/10.3390/biology12030393">10.3390/biology12030393</a><br><br><h5>Additional Links</h5>https://www.mdpi.com/2079-7737/12/3/393</span>
kaust.acknowledged.supportUnitBaseline fund
kaust.acknowledged.supportUnitOffice of Sponsored Research (OSR)
kaust.grant.numberFCC/1/1976-25
kaust.grant.numberREI/1/4446-01
kaust.personArold, Stefan T.
orcid.authorAdisornkanj, Ploy::0000-0002-8096-8809
orcid.authorChanprasit, Rajit
orcid.authorEliason, Steven
orcid.authorFons, Juan M.::0000-0002-6044-1989
orcid.authorIntachai, Worrachet
orcid.authorTongsima, Sissades
orcid.authorOlsen, Bjorn
orcid.authorArold, Stefan T.::0000-0001-5278-0668
orcid.authorNgamphiw, Chumpol::0000-0002-8581-397X
orcid.authorAmendt, Brad A.
orcid.authorTucker, Abigail S.::0000-0001-8871-6094
orcid.authorKantaputra, Piranit::0000-0001-9841-0881
orcid.id0000-0001-9841-0881
orcid.id0000-0001-8871-6094
orcid.id0000-0002-8581-397X
orcid.id0000-0001-5278-0668
orcid.id0000-0002-6044-1989
orcid.id0000-0002-8096-8809
refterms.dateFOA2023-03-05T09:57:27Z
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