Mutations in the WLS are associated with dental anomalies, torus palatinus, and torus mandibularis

Abstract

Summary Background Canonical and non-canonical WNT signaling are important for odontogenesis. WNT ligand secretion mediator (WLS; MIM611514) is required to transport lipid-modified WNT proteins from the Golgi to the cell membrane, where canonical and non-canonical WNT proteins are released into the extracellular milieu. Biallelic pathogenic variants in WLS are implicated in autosomal recessive Zaki syndrome (ZKS; MIM 619648), the only genetic condition known to be caused by pathogenic variants in WLS. Objective To investigate molecular etiology of dental anomalies in 250 patients with or without oral exostoses. Patients and methods Clinical and radiographic examination, and whole exome sequencing, were performed in the case of 250 patients with dental anomalies with or without oral exostoses. Results Four extremely rare heterozygous missense variants (p.Ile20Thr, p.Met46Leu, p.Ser453Ile and p.Leu516Phe) in WLS were identified in 11 patients with dental anomalies. In five of these patients, a torus palatinus or a torus mandibularis was observed. Conclusion We report for the first time the heterozygous WLS variants in patients with dental anomalies. Root maldevelopments in patients with WLS variants supports the role of canonical and non-canonical WNT signaling in root development. We also show that variants in WLS were implicated in torus palatinus and torus mandibularis. In addition, this is the first time that heterozygous carriers of WLS variants were found to manifest phenotypes. WLS variants were likely to have adverse effects on the concentration of WNT ligands delivered to the cell membrane, resulting in aberrant canonical and non-canonical WNT signaling, and subsequent phenotypes. Limitations of the study Patient’s positioning during the acquisition of panoramic radiography might have affected the appearance of the tooth structures. If we had all family members of each patient to study co-segregation between genotype and phenotype, it would have strengthened the association of WLS variants and the phenotypes.

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

“…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.…”

“…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.…”

“…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.…”

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

“…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.…”

“…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 ].…”