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Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.

ABSTRACT: 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.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.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.Mutations in LRP6 cause TA in humans.Genet Med 18 11, 1158-1162.

SUBMITTER: Ockeloen CW

PROVIDER: S-EPMC5018235 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.

Ockeloen Charlotte W CW Khandelwal Kriti D KD Dreesen Karoline K Ludwig Kerstin U KU Sullivan Robert R van Rooij Iris A L M IALM Thonissen Michelle M Swinnen Steven S Phan Milien M Conte Federica F Ishorst Nina N Gilissen Christian C RoaFuentes Laury L van de Vorst Maartje M Henkes Arjen A Steehouwer Marloes M van Beusekom Ellen E Bloemen Marjon M Vankeirsbilck Bruno B Bergé Stefaan S Hens Greet G Schoenaers Joseph J Poorten Vincent Vander VV Roosenboom Jasmien J Verdonck An A Devriendt Koen K Roeleveldt Nel N Jhangiani Shalini N SN Vissers Lisenka E L M LELM Lupski James R JR de Ligt Joep J Von den Hoff Johannes W JW Pfundt Rolph R Brunner Han G HG Zhou Huiqing H Dixon Jill J Mangold Elisabeth E van Bokhoven Hans H Dixon Michael J MJ Kleefstra Tjitske T Hoischen Alexander A Carels Carine E L CEL

Genetics in medicine : official journal of the American College of Medical Genetics 20160310 11

<h4>Purpose</h4>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.<h4>Methods</h4>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 wit ...[more]

PMID: 26963285

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Project description:Since MSX1 and PAX9 are linked to the pathogenesis of nonsyndromic tooth agenesis, we performed detailed mutational analysis of these two genes sampled from Japanese patients. We identified two novel MSX1 variants with an amino acid substitution within the homeodomain; Thr174Ile (T174I) from a sporadic hypodontia case and Leu205Arg (L205R) from a familial oligodontia case. Both the Thr174 and Leu205 residues in the MSX1 homeodomain are highly conserved among different species. To define possible roles of mutations at these amino acids in the pathogenesis of nonsyndromic tooth agenesis, we performed several functional analyses. It has been demonstrated that MSX1 plays a pivotal role in hard tissue development as a suppressor for mesenchymal cell differentiation. To evaluate the suppression activity of the variants in mesenchymal cells, we used the myoD-promoter, which is one of convenient reporter assay system for MSX1. Although the gene products of these MSX1 variants are stable and capable of normal nuclear localization, they do not suppress myoD-promoter activity in differentiated C2C12 cells. To clarify the molecular mechanisms underlying our results, we performed further analyses including electrophoretic mobility shift assays, and co-immunoprecipitation assays to survey the molecular interactions between the mutant MSX1 proteins and the oligonucleotide DNA with MSX1 consensus binding motif or EZH2 methyltransferase. Since EZH2 is reported to interact with MSX1 and regulate MSX1 mediated gene suppression, we hypothesized that the T174I and L205R substitutions would impair this interaction. We conclude from the results of our experiments that the DNA binding ability of MSX1 is abolished by these two amino acid substitutions. This illustrates a causative role of the T174I and L205R MSX1 homeodomain mutations in tooth agenesis, and suggests that they may influence cell proliferation and differentiation resulting in lesser tooth germ formation in vivo.

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Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.

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Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.

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