Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis
Open accessAbstract
Purpose We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients. Methods WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls. Results We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo. Conclusion Mutations in LRP6 cause TA in humans.Genet Med 18 11, 1158-1162.
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The effect of this presumably dominant-negative mutation on early development may be more widespread than that of previously described pathogenic LRP6 variants.
“Therefore, the effect of this presumably dominant-negative mutation on early development may be more widespread than that of previously described pathogenic LRP6 variants [54,55].”
From Molecular Pathway-Based Classification of Ectodermal Dysplasias: First Five-Yearly Update (2022) · cites this paper as [54]
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- Authors
- Ockeloen, C. W., Khandelwal, K. D., Dreesen, K., Ludwig, K. U., Sullivan, R., van Rooij, I. A. L. M., Thonissen, M., Swinnen, S., Phan, M., Conte, F., Ishorst, N., Gilissen, C., Roa Fuentes, L., van de Vorst, M., Henkes, A., Steehouwer, M., van Beusekom, E., Bloemen, M., Vankeirsbilck, B., Bergé, S., Hens, G., Schoenaers, J., Vander Poorten, V., Roosenboom, J., Verdonck, A., Devriendt, K., Roeleveldt, N., Jhangiani, S. N., Vissers, L. E. L. M., Lupski, J. R., de Ligt, J., Von den Hoff, J. W., Pfundt, R., Brunner, H. G., Zhou, H., Dixon, J., Mangold, E., van Bokhoven, H., Dixon, M. J., Kleefstra, T., Hoischen, A., & Carels, C. E. L.
- Affiliations
- Radboud University Medical Center (NL)
- University of Bonn (DE)
- University of Manchester (GB)
- KU Leuven (BE)
- Radboud University Nijmegen (NL)
- Universitair Ziekenhuis Leuven (BE)
- Baylor College of Medicine (US)
- Corresponding author
- Hoischen, Alexander
- Carels, Carine E.L.
- ORCID
- Ockeloen, Charlotte W.
- Ludwig, Kerstin U.
- Conte, Federica
- Ishorst, Nina
- Gilissen, Christian
- Steehouwer, Marloes
- Vankeirsbilck, Bruno
- Bergé, Stefaan
- Hens, Greet
- Vander Poorten, Vincent
- Roosenboom, Jasmien
- Jhangiani, Shalini N.
- Vissers, Lisenka E.L.M.
- Lupski, James R.
- Pfundt, Rolph
- Brunner, Han G.
- Zhou, Huiqing
- Dixon, Jill
- Mangold, Elisabeth
- Dixon, Michael J.
- Kleefstra, Tjitske
- Hoischen, Alexander
- Carels, Carine E.L.
- Venue
- Genetics in Medicine
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 18
- Issue
- 11
- Pages
- 1158-1162
- ISSN
- 1098-3600 (ISSN-L)
- PMC
- PMC5018235
- OpenAlex
- W2294599644
- Cited by
- 78
- References
- 2
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 7 · 2023: 4 · 2022: 10 · 2021: 11 · 2020: 8 · 2019: 7 · 2018: 8 · 2017: 5 · 2016: 6
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Genetics in Medicine (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Lirias (KU Leuven) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- European Orthodontic Society
- National Institutes of Health (RO1NS058529)
- Medical Research Council (MR/M012174/1)
- Biotechnology and Biological Sciences Research Council (1085997)
- National Human Genome Research Institute (U54HG006542, UM1HG006542)
- National Institute of Neurological Disorders and Stroke (R01NS058529)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Cleft Lip and Palate Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
- Keywords
- tooth agenesis, orofacial clefts, LRP6, Wnt signaling, genetic mutations, frameshift mutation, splice site mutation, missense mutations, de novo mutations, dominant inheritance
- MeSH terms
- Adolescent, Anodontia, Child, Female, Humans, Male, Pedigree, Frameshift Mutation, Sequence Analysis, DNA, Genetic Predisposition to Disease, Mutation, Missense, Exome, Wnt Signaling Pathway, Low Density Lipoprotein Receptor-Related Protein-6
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