Mutations in LRP6 highlight the role of WNT signaling in oral exostoses and dental anomalies

Kantaputra, Piranit Nik; Jatooratthawichot, Peeranat; Jintakanon, Kanoknart; Intachai, Worrachet; Pradermdutsadeeporn, Prapat; Adisornkanj, Ploy; Tongsima, Sissades; Ngamphiw, Chumpol; Olsen, Bjørn R.; Tucker, Abigail S.; Cairns, James R. Ketudat

doi:10.1016/j.archoralbio.2022.105514

Cited by 13 publications

(15 citation statements)

References 43 publications

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“…The Wnt–β-catenin signaling pathway is known to be crucial for tooth development and overactivation of Wnt/β-catenin signaling results in supernumerary tooth formation or odontoma [ 96 ] ( Figure 11 ). The association of genetic variants in Wnt/β-catenin signaling pathway and mesiodens formation [ 46 , 47 , 48 ] suggests the mutations in PTPN23 in our patients were upstream of the Wnt/β-catenin signaling pathway in the pathogenetic process.…”

Section: Discussionmentioning

confidence: 99%

“…These problems have made gene hunting for mesiodens phenotypes complicated and unsuccessful. However, recently genetic variants in LRP4 , LRP5 , LRP6 , WLS, and DKK1 have been reported to be implicated in mesiodens with or without oral exostoses, including torus palatinus, torus mandibularis, and buccal exosteses [ 46 , 47 , 48 , 49 , 50 ]. We were very fortunate to meet a large Hmong family living in Chiang Rai, a province at the border of Thailand and Myanmar.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, mesiodens have been reported in a number of patients with Nance–Horan syndrome [ 41 , 42 , 43 , 44 ] and holoprosencephaly [ 45 ]. Recently genetic variants in the WNT/β-catenin signaling pathway, including LRP4 , LRP5 , LRP6 , WLS , and DKK1 , have been demonstrated to be implicated in mesiodens phenotype [ 46 , 47 , 48 , 49 , 50 ]. The objective of our study was to investigate the genetic etiology of mesiodens in a two-generation Hmong family.…”

Section: Introductionmentioning

confidence: 99%

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

Adisornkanj

Chanprasit²,

Eliason

et al. 2023

Biology

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Adisornkanj

Chanprasit²,

Eliason

et al. 2023

Biology

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“…Mesiodens and supernumerary teeth generally are not present in the same persons. A large number of mesiodens are inverted or unerupted [ 21 , 22 , 23 , 24 , 25 ]. Mesiodens is a genetically heterogeneous dental malformation.…”

Section: Introductionmentioning

confidence: 99%

“…Mesiodens is a genetically heterogeneous dental malformation. Recently, genetic variants in LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 5 ( LRP5; MIM 603506), LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 6 ( LRP6 ; MIM 603507), WNT LIGAND SECRETION MEDIATOR (WLS; MIM 611514), DICKKOPF WNT SIGNALING PATHWAY INHIBITOR 1 (DKK1; MIM 605189), and LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 4 (LRP4; MIM 604270) have been reported to be implicated in mesiodens with or without oral exostoses [ 21 , 22 , 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Heterozygous Variants in FREM2 Are Associated with Mesiodens, Supernumerary Teeth, Oral Exostoses, and Odontomas

et al. 2023

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Background: Supernumerary teeth refer to extra teeth that exceed the usual number of dentitions. A mesiodens is a particular form of supernumerary tooth, which is located in the premaxilla region. The objective of the study was to investigate the genetic etiology of extra tooth phenotypes, including mesiodens and isolated supernumerary teeth. Methods: Oral and radiographic examinations and whole-exome sequencing were performed on every patient in our cohort of 122 patients, including 27 patients with isolated supernumerary teeth and 94 patients with mesiodens. A patient who had multiple supernumerary teeth also had odontomas. Results: We identified a novel (c.8498A>G; p.Asn2833Ser) and six recurrent (c.1603C>T; p.Arg535Cys, c.5852G>A; p.Arg1951His, c.6949A>T; p.Thr2317Ser; c.1549G>A; p.Val517Met, c.1921A>G; p.Thr641Ala, and c.850G>C; p.Val284Leu) heterozygous missense variants in FREM2 in eight patients with extra tooth phenotypes. Conclusions: Biallelic variants in FREM2 are implicated in autosomal recessive Fraser syndrome with or without dental anomalies. Here, we report for the first time that heterozygous carriers of FREM2 variants have phenotypes including oral exostoses, mesiodens, and isolated supernumerary teeth.

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Clefting, Dental, and Craniofacial Syndromes

Kantaputra,

Marazita

2025

Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics

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Mutations in LRP6 highlight the role of WNT signaling in oral exostoses and dental anomalies

Cited by 13 publications

References 43 publications

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

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

Heterozygous Variants in FREM2 Are Associated with Mesiodens, Supernumerary Teeth, Oral Exostoses, and Odontomas

Clefting, Dental, and Craniofacial Syndromes

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