title: 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.
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine, University Medical Centre Utrecht, 3508 AB Utrecht, the Netherlands.
authors.forename: Maarten P G
authors.initials: MP
authors.lastname: Massink
authors.affiliation: Department of Oral and Maxillofacial Surgery, Prosthodontics and Special Dental Care, University Medical Centre Utrecht, 3508 AB Utrecht, the Netherlands.
authors.forename: Marijn A
authors.initials: MA
authors.lastname: Créton
authors.affiliation: Department of Cell Biology, Centre for Molecular Medicine, University Medical Centre Utrecht, 3584 CX Utrecht, the Netherlands.
authors.forename: Francesca
authors.initials: F
authors.lastname: Spanevello
authors.affiliation: Department of Oral and Maxillofacial Surgery, Prosthodontics and Special Dental Care, University Medical Centre Utrecht, 3508 AB Utrecht, the Netherlands.
authors.forename: Willem M M
authors.initials: WM
authors.lastname: Fennis
authors.affiliation: Department of Fixed and Removable Prosthodontics, Centre for Dentistry and Oral Hygiene, University Medical Centre Groningen, 9700 RB Groningen, the Netherlands; Antonius Hospital, 3435 CM Nieuwegein, the Netherlands.
authors.forename: Marco S
authors.initials: MS
authors.lastname: Cune
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine, University Medical Centre Utrecht, 3508 AB Utrecht, the Netherlands.
authors.forename: Sanne M C
authors.initials: SM
authors.lastname: Savelberg
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine, University Medical Centre Utrecht, 3508 AB Utrecht, the Netherlands.
authors.forename: Isaäc J
authors.initials: IJ
authors.lastname: Nijman
authors.affiliation: Department of Cell Biology, Centre for Molecular Medicine, University Medical Centre Utrecht, 3584 CX Utrecht, the Netherlands.
authors.forename: Madelon M
authors.initials: MM
authors.lastname: Maurice
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine, University Medical Centre Utrecht, 3508 AB Utrecht, the Netherlands.
authors.forename: Marie-José H
authors.initials: MJ
authors.lastname: van den Boogaard
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine, University Medical Centre Utrecht, 3508 AB Utrecht, the Netherlands. Electronic address: g.vanhaaften@umcutrecht.nl.
authors.forename: Gijs
authors.initials: G
authors.lastname: van Haaften
mesh_terms: D000848:Anodontia / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D057809:HEK293 Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D051153:Wnt Proteins / Q000235:genetics*
chemical_list: C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051153:Wnt Proteins