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

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

doi:10.3390/biology12030393

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

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

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2 Scopus citations

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.

Original language	English (US)
Pages (from-to)	393
Journal	Biology
Volume	12
Issue number	3
DOIs	https://doi.org/10.3390/biology12030393
State	Published - Mar 1 2023

Bibliographical note

KAUST Repository Item: Exported on 2023-03-06
Acknowledged KAUST grant number(s): FCC/1/1976-25, REI/1/4446-01
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.

ASJC Scopus subject areas

General Agricultural and Biological Sciences
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.3390/biology12030393

https://repository.kaust.edu.sa/bitstream/10754/689986/1/biology-12-00393-v2.pdf

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@article{c7d13b4e913c433abd4e5e4f4e4d9548,

title = "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.",

author = "Ploy Adisornkanj and Rajit Chanprasit and Steven Eliason and Fons, {Juan M.} and Worrachet Intachai and Sissades Tongsima and Bjorn Olsen and Arold, {Stefan T.} and Chumpol Ngamphiw and Amendt, {Brad A.} and Tucker, {Abigail S.} and Piranit Kantaputra",

note = "KAUST Repository Item: Exported on 2023-03-06 Acknowledged KAUST grant number(s): FCC/1/1976-25, REI/1/4446-01 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.",

year = "2023",

month = mar,

day = "1",

doi = "10.3390/biology12030393",

language = "English (US)",

volume = "12",

pages = "393",

journal = "Biology",

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TY - JOUR

T1 - Genetic Variants in Protein Tyrosine Phosphatase Non-Receptor Type 23 Are Responsible for Mesiodens Formation

AU - Adisornkanj, Ploy

AU - Chanprasit, Rajit

AU - Eliason, Steven

AU - Fons, Juan M.

AU - Intachai, Worrachet

AU - Tongsima, Sissades

AU - Olsen, Bjorn

AU - Arold, Stefan T.

AU - Ngamphiw, Chumpol

AU - Amendt, Brad A.

AU - Tucker, Abigail S.

AU - Kantaputra, Piranit

N1 - KAUST Repository Item: Exported on 2023-03-06 Acknowledged KAUST grant number(s): FCC/1/1976-25, REI/1/4446-01 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.

PY - 2023/3/1

Y1 - 2023/3/1

N2 - 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.

AB - 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.

UR - http://hdl.handle.net/10754/689986

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

U2 - 10.3390/biology12030393

DO - 10.3390/biology12030393

M3 - Article

C2 - 36979085

SN - 2079-7737

VL - 12

SP - 393

JO - Biology

JF - Biology

IS - 3

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

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