Mutations in LRP5 and BMP4 are associated with mesiodens, tooth agenesis, root malformation, and oral exostoses

Abstract

WNT/β-catenin and BMP signaling pathways play important roles in the process of tooth development. Dysregulation of WNT/β-catenin and BMP signaling is implicated in a number of human malformations, including dental anomalies.Whole exome and Sanger sequencing identified seven patients with LRP5 mutations (p. Asn1121Asp, p.Asp856Asn, p.Val1433Met, and p.Val1245Met) and six patients with BMP4 mutations (p.Asn150Lys, p.Gly168Arg, p.Arg269Gln, and p.Ala42Glu). All patients were affected with isolated dental anomalies (dental anomalies with no other structural defects), including mesiodens, tooth agenesis, unseparated roots, narrow roots, shortened and tapered roots, and taurodontism.Five patients with LRP5 and one with BMP4 mutations had oral exostoses. Protein models of LRP5 mutations indicate the possible functional effects of the mutations. Here we report for the first time that mutations in LRP5 are associated with dental anomalies. LRP5 appears to be the first gene related to pathogenesis of mesiodens. We also show for the first time that in addition to tooth agenesis, mutations in BMP4 are also implicated in root maldevelopment and torus mandibularis. Sharing of the phenotypes of the patients with LRP5 and BMP4 mutations, which include root maldevelopment, tooth agenesis, and torus mandibularis, implicates cross talks between the WNT/β-catenin and BMP signaling pathways, especially during root development.

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

“…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.…”

“…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.…”

“…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 ].…”