Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSX1, and PAX9 genes

Bergendal, Birgitta; Klar, Joakim; Stecksén‐Blicks, Christina; Norderyd, Johanna; Dahl, Niklas

doi:10.1002/ajmg.a.34045

Cited by 127 publications

(112 citation statements)

References 43 publications

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“…25 MSX1 and non-syndromic tooth agenesis Non-syndromic tooth agenesis (ns TA) is another common developmental anomaly that can be caused by MSX1 variants. 14 To date, nearly 20 MSX1 mutations have been related to ns TA 8,13,[26][27][28][29][30][31][32][33][34][35][36][37] (Table 2). Functional analyses of the mutant proteins suggest that haploinsufficiency of MSX1 underlies this phenotype.…”

Section: Disease Phenotypes Caused By Msx1 Mutationsmentioning

confidence: 99%

MSX1 mutations and associated disease phenotypes: genotype-phenotype relations

Liang

Hoff

Lange³

et al. 2016

Eur J Hum Genet

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The Msx1 transcription factor is involved in multiple epithelial-mesenchymal interactions during vertebrate embryogenesis. It has pleiotropic effects in several tissues. In humans, MSX1 variants have been related to tooth agenesis, orofacial clefting, and nail dysplasia. We correlate all MSX1 disease causing variants to phenotypic features to shed light on this hitherto unclear association. MSX1 truncations cause more severe phenotypes than in-frame variants. Mutations in the homeodomain always cause tooth agenesis with or without other phenotypes while mutations outside the homeodomain are mostly associated with non-syndromic orofacial clefts. Downstream effects can be further explored by the edgetic perturbation model. This information provides new insights for genetic diagnosis and for further functional analysis of MSX1 variants.

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Section: Disease Phenotypes Caused By Msx1 Mutationsmentioning

confidence: 99%

MSX1 mutations and associated disease phenotypes: genotype-phenotype relations

Liang

Hoff

Lange³

et al. 2016

Eur J Hum Genet

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“…Axin1 was found to be methylated in a pair of discordant monozygotic twins with caudal duplication anomaly (OMIM: 607864) (337). Supporting the critical role of Axin2 in craniofacial development, multiple studies in humans have identified polymorphisms/mutations in Axin2 related to tooth agenesis (338)(339)(340)(341) and oral clefts (132,340). Mutations in Axin2 are also associated with oligodontia-colorectal cancer syndrome (Arg656X) (OMIM: 608615) (338).…”

Section: Axinmentioning

confidence: 99%

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

2013

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The Wnt signaling pathway plays key roles in differentiation and development and alterations in this signaling pathway are causally associated with numerous human diseases. While several laboratories were examining roles for Wnt signaling in skeletal development during the 1990s, interest in the pathway rose exponentially when three key papers were published in 2001-2002. One report found that loss of the Wnt co-receptor, Low-density lipoprotein related protein-5 (LRP5), was the underlying genetic cause of the syndrome Osteoporosis pseudoglioma (OPPG). OPPG is characterized by early-onset osteoporosis causing increased susceptibility to debilitating fractures. Shortly thereafter, two groups reported that individuals carrying a specific point mutation in LRP5 (G171V) develop high-bone mass. Subsequent to this, the causative mechanisms for these observations heightened the need to understand the mechanisms by which Wnt signaling controlled bone development and homeostasis and encouraged significant investment from biotechnology and pharmaceutical companies to develop methods to activate Wnt signaling to increase bone mass to treat osteoporosis and other bone disease. In this review, we will briefly summarize the cellular mechanisms underlying Wnt signaling and discuss the observations related to OPPG and the high-bone mass disorders that heightened the appreciation of the role of Wnt signaling in normal bone development and homeostasis. We will then present a comprehensive overview of the core components of the pathway with an emphasis on the phenotypes associated with mice carrying genetically engineered mutations in these genes and clinical observations that further link alterations in the pathway to changes in human bone. Keywords: Wnt signaling; mouse models; Lrp5/Lrp6; β-catenin; skeletal phenotypes Bone Research (2013) 1: 27-71. doi: 10.4248/BR201301004 Overview of Wnt signal transductionWnts are a family of 19 mammalian proteins characterized by a conserved pattern of cysteine residues( 1). Wnts can activate several signaling pathways after binding to their cognate receptors, however, the bulk of this review will focus on the best characterized of these pathways, the so-called canonical pathway (Figure 1). This pathway results in the stabilization of the β-catenin protein and subsequent transactivation of target genes (2). It is initiated by Wnt ligands binding to a receptor complex that includes a member of the Frizzled (Fzd) family of seven-transmembrane receptors and either Lrp5, or the related Lrp6 protein(3). Engagement of this complex results in the phosphorylation of the cytoplasmic domain of Lrp5 or Lrp6, creating a binding site for the Axin protein.In the absence of an upstreamsignal, Axin exists in a multiprotein complex that also includes Adenomatous polyposis coli (APC) and the serine/ threonine protein kinase, Glycogen synthase kinase 3 α/β. This complex facilitates β-catenin for GSK3-dependent phosphorylation, targeting it for ubiquitin-depen- 28 dent proteolysis. Binding of Axin to phosphoryl...

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“…1 As tooth formation shares mechanisms with the development of other ectodermal appendages, TA often occurs as part of a variety of ectodermal dysplasia (ED) syndromes including Witkop syndrome, hypohydrotic ectodermal dysplasia, odonto-onycho-dermal dysplasia (OODD), Schöpf-Schulz-Passarge syndrome (SSPS) and others. For these human TA syndromes, mutations have been identified, respectively, in MSX1, 2 EDA, EDAR, 3-5 EDARADD, 6 and WNT10A. 7,8 WNT10A mutations were identified in a family of which four members were affected with isolated TA or microdontia, 9 whereas more recently in a larger cohort of 34 patients with isolated TA, 56% appeared to have WNT10A mutations.…”

Section: Introductionmentioning

confidence: 99%

Variability in dentofacial phenotypes in four families with WNT10A mutations

et al. 2014

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This article describes the inter-and intra-familial phenotypic variability in four families with WNT10A mutations. Clinical characteristics of the patients range from mild to severe isolated tooth agenesis, over mild symptoms of ectodermal dysplasia, to more severe syndromic forms like odonto-onycho-dermal dysplasia (OODD) and Schö pf-Schulz-Passarge syndrome (SSPS). Recurrent WNT10A mutations were identified in all affected family members and the associated symptoms are presented with emphasis on the dentofacial phenotypes obtained with inter alia three-dimensional facial stereophotogrammetry. A comprehensive overview of the literature regarding WNT10A mutations, associated conditions and developmental defects is presented. We conclude that OODD and SSPS should be considered as variable expressions of the same WNT10A genotype. In all affected individuals, a dished-in facial appearance was observed which might be helpful in the clinical setting as a clue to the underlying genetic etiology.

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Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSX1, and PAX9 genes

Cited by 127 publications

References 43 publications

MSX1 mutations and associated disease phenotypes: genotype-phenotype relations

MSX1 mutations and associated disease phenotypes: genotype-phenotype relations

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

Variability in dentofacial phenotypes in four families with WNT10A mutations

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