Loss-of-Function Mutations in the WNT Co-receptor LRP6 Cause Autosomal-Dominant Oligodontia

Abstract

Tooth agenesis is one of the most common developmental anomalies in man. Oligodontia, a severe form of tooth agenesis, occurs both as an isolated anomaly and as a syndromal feature. We performed exome sequencing on 20 unrelated individuals with apparent non-syndromic oligodontia and failed to detect mutations in genes previously associated with oligodontia. In three of the probands, we detected heterozygous variants in LRP6, and sequencing of additional oligodontia-affected individuals yielded one additional mutation in LRP6. Three mutations (c.1144_1145dupAG [p.Ala383Glyfs(∗)8], c.1779dupT [p.Glu594(∗)], and c.2224_2225dupTT [p.Leu742Phefs(∗)7]) are predicted to truncate the protein, whereas the fourth (c.56C>T [p.Ala19Val]) is a missense variant of a conserved residue located at the cleavage site of the protein's signal peptide. All four affected individuals harboring a LRP6 mutation had a family history of tooth agenesis. LRP6 encodes a transmembrane cell-surface protein that functions as a co-receptor with members from the Frizzled protein family in the canonical Wnt/β-catenin signaling cascade. In this same pathway, WNT10A was recently identified as a major contributor in the etiology of non-syndromic oligodontia. We show that the LRP6 missense variant (c.56C>T) results in altered glycosylation and improper subcellular localization of the protein, resulting in abrogated activation of the Wnt pathway. Our results identify LRP6 variants as contributing to the etiology of non-syndromic autosomal-dominant oligodontia and suggest that this gene is a candidate for screening in DNA diagnostics.

Mutation of KREMEN1, a modulator of Wnt signaling, is responsible for ectodermal dysplasia including oligodontia in Palestinian families

“…21,22 Mesenchymalspecific elimination of β-catenin causes arrest of tooth development at the bud stage, indicating that Wnt signaling has a role in the transition from the bud to cap stage of developing dental mesenchyme. 23 Given the known involvement of WNT10A and LRP6 in tooth development and of pathogenic variants in these genes in oligodontia, 2,24 it is not surprising that mutant KREMEN1 also has a role. We speculate that the substitution of serine for phenylalanine in the KREMEN1 WSC extracellular domain interferes with KREMEN1 regulation of Wnt signaling, either as a positive or as a negative regulator, or possibly both at different stages of development.…”

“…14 This observation is consistent with the finding that oligodontia and ectodermal dysplasias can be caused by reduced Wnt-β-catenin signaling due to pathogenic variants in WNT10A and LRP6. 2,[25][26][27] In addition, pathogenic variants in EDA, a downstream target of Wnt/β-catenin signaling, cause X-linked ectodermal dysplasia 28 and non-syndromic hypodontia. 29 On the other hand, deletion of the WSC domain in KREMEN2 abolishes Dickkopf-1 binding and maintains Wnt signaling, 11 which is consistent with the finding that protein-truncating variants in the negative Wnt regulator Axin-2 give rise to autosomal dominant hypodontia.…”

“…Genes responsible for non-syndromic oligodontia, which is generally dominantly inherited, include MSX1 (MIM 142983), PAX9 (MIM 167416), WNT10A (MIM 606268), EDA1 (MIM 300451), and LRP6. 2 In contrast, syndromic oligodontia is more often recessively inherited and appears in the context of multiple congenital malformations, reflecting shared developmental pathways of teeth with other orofacial and ectodermal structures. 3 Syndromic oligodontia is often a feature of ectodermal dysplasias, which involve anomalies of hair, nails, and sweat glands, in addition to teeth.…”

Mutations in WNT10B Are Identified in Individuals with Oligodontia

“…Mutations 4 Recently, multiple mutations in LRP6 (low density lipoprotein receptor-related protein 6 [MIM: 603507]), encoding a co-receptor in the Wnt pathway, were also found to cause autosomal-dominant oligodontia. 5 By Sanger sequencing of these oligodontia-associated genes, we have previously identified mutations in most of these genes in Chinese individuals with non-syndromic oligodontia. [6][7][8][9][10] However, no mutations were detected in nearly half of the examined affected individuals, suggesting the existence of unidentified genetic etiologies.…”

Intrinsic disorder in spondins and some of their interacting partners

“…Regions 95-100 and 147-152 of Fzd8 are involved in Wnt binding, motif Lys-Thr-X-X-X-Trp located at 608-613 region mediates interaction with the PDZ domain of Dvl family members, and a PDZ-binding motif is located the very end of C-terminus (residues 692-694). Figure 9B shows that Fzd8 is predicted to have several IDPRs (residues 1-33, 156-249, 340-380, 516-526, 574-580, and 625-694) 4 disorder-based potential binding sites (residues [148][149][150][151][152][153][154][155][156][157][158][159][160][196][197][198][199][200][201][202][203][204][205][206][207][208][209][210], 666-679, and 687-694), and several phosphorylation sites. Two functional motifs/regions of Fzd8 (one of the Dvl binding motifs (residues 147-152) and C-terminal PDZ-binding motif) are located within the disordered regions that are expected to undergo binding-induced disorder-to-order transitions, clearly indicating that intrinsic disorder is important for the functionality of this transmembrane protein (see Fig.…”