Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis
Ockeloen, Charlotte W.; Khandelwal, Kriti D.; Dreesen, Karoline; Ludwig, Kerstin U.; Sullivan, Robert; Van Rooij, Iris A L M; Thonissen, Michelle; Swinnen, Steven; Phan, Milien; Conte, Federica; Ishorst, Nina; Gilissen, Christian; Roa Fuentes, Laury; Van De Vorst, Maartje; Henkes, Arjen; Steehouwer, Marloes; Van Beusekom, Ellen; Bloemen, Marjon; Vankeirsbilck, Bruno; Bergé, Stefaan; Hens, Greet; Schoenaers, Joseph; Vander Poorten, Vincent; Roosenboom, Jasmien; Verdonck, An; Devriendt, Koen; Roeleveldt, Nel; Jhangiani, Shalini N.; Vissers, Lisenka E L M; Lupski, James R.; De Ligt, Joep; Von Den Hoff, Johannes W.; Pfundt, Rolph; Brunner, Han G.; Zhou, Huiqing; Dixon, Jill; Mangold, Elisabeth; Van Bokhoven, Hans; Dixon, Michael J.; Kleefstra, Tjitske; Hoischen, Alexander; Carels, Carine E L
(2016) Genetics in Medicine, volume 18, issue 11, pp. 1158 - 1162
(Article)
Abstract
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
... read more
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.
show less
Download/Full Text
The full text of this publication is not available.
Keywords: LRP6, molecular inversion probes, tooth agenesis, Wnt/β-catenin canonical signaling pathway, Genetics(clinical), Journal Article
ISSN: 1098-3600
Publisher: Lippincott Williams and Wilkins
(Peer reviewed)