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

Maarten P G Massink, Marijn A. Creton, Francesca Spanevello, Willem M M Fennis, Marco S. Cune, Sanne M C Savelberg, Isaäc J. Nijman, Madelon M. Maurice, Marie José H vandenBoogaard, Gijs van Haaften

Research output: Contribution to journalArticleAcademicpeer-review


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<sup>*</sup>8], c.1779dupT [p.Glu594<sup>*</sup>], and c.2224_2225dupTT [p.Leu742Phefs<sup>*</sup>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.

Original languageEnglish
Pages (from-to)621–626
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 2015


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