A novel <i>MSX1</i> mutation in hypodontia

Muynck, S De; Schollen, E; Matthijs, Gert; Verdonck, Anna; Devriendt, Koenraad; Carels, Carine

doi:10.1002/ajmg.a.30181

Cited by 80 publications

(61 citation statements)

References 18 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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“…These phenotypes include cleft palate, an absence of alveolar processes, and an arrest of tooth development at the bud stage, thus predicting the phenotype observed in humans carrying MSX1 mutations. Mutations in MSX1, a non-clustered homeobox protein, have been reported previously in families with autosomal dominant hypodontia (Vastardis et al 1996;van den Boogaard et al 2000;Jumlongras et al 2001;Lidral and Reising 2002;Jezewski et al 2003;De Muynck et al 2004). The present study presents the first mutation identified in a Pakistani family with autosomal recessive hypodontia with associated dental anomalies.…”

Section: Discussionmentioning

confidence: 89%

“…Environmental factors include radiation therapy, chemotherapeutic agents and use of thalidomide during pregnancy (Axrup et al 1966;Maguire et al 1987;Nasman et al 1997). In the majority of familial cases of hypodontia alone or its association with other anomalies, the mode of inheritance is autosomal dominant (Vastardis et al 1996;van den Boogaard et al 2000;Jumlongras et al 2001;Lidral and Reising 2002;Jezewski et al 2003;De Muynck et al 2004). An autosomal recessive model of hypodontia with associated anomalies was reported in a large family by Ahmad et al (1998).…”

Section: Introductionmentioning

confidence: 99%

A novel missense mutation in MSX1 underlies autosomal recessive oligodontia with associated dental anomalies in Pakistani families

et al. 2006

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Tooth agenesis constitutes the most common anomaly of dental development in humans. In the majority of familial cases of hypodontia alone or in association with other anomalies, the mode of inheritance is autosomal dominant. In the present study, we have identified two distantly related consanguineous Pakistani kindreds with an autosomal recessive form of oligodontia with associated dental anomalies. Locus in this case has been mapped on chromosome 4p16.1-p16.3. The maximum two-point LOD score of 2.85 (h=0.0) was obtained at markers D4S2925 and D4S2285. A maximum multipoint LOD score exceeding 4 was obtained at the same markers. Recombination events observed in affected individuals localized the disease locus between markers D4S412 and D4S2935, spanning a 9.24-cM region on chromosome 4p16.1-p16.3. Sequence analysis of candidate gene MSX1 revealed a novel recessive missense mutation resulting in substitution of alanine to threonine amino acid (p. A219T), located in the MSX1 homeodomain, which is important for DNA binding and proteinprotein interaction. The mutation, p. A219T, is the first recessive mutation identified in MSX1.

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“…2,3 In humans, multiple MSX1 mutations have been identified in families exhibiting Mendelian inheritance of an oligodontia phenotype (either non-syndromic or syndromic). [3][4][5][6][7][8][9][10][11][12][13][14] However, MSX1 also clearly affects the common human oral cleft phenotypes, as demonstrated through multiple genetic studies. [15][16][17][18][19][20] Yet, in all but a single case report, 5 MSX1 apparently functions as a complex disease determinant for oral clefting.…”

Section: Introductionmentioning

confidence: 99%

Clinical and functional data implicate the Arg(151)Ser variant of MSX1 in familial hypodontia

et al. 2011

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Multiple previous reports confirm that several missense alleles of MSX1 exhibit Mendelian inheritance of an oligodontia phenotype (agenesis of more than six secondary teeth besides third molars). However, the extent to which missense MSX1 alleles contribute to common, multifactorial disorders is less certain. It is still not yet clear whether multiple non-synonomous MSX1-coding variants identified among patients with oral clefting are merely neutral polymorphisms or whether any of these might represent real mutations with mild effects. The present work steps toward resolving these issues for at least one MSX1 allele: R151S, previously identified in a single Japanese proband with unilateral cleft lip and palate. Candidate gene sequencing within a patient cohort demonstrating mild tooth agenesis (loss of six or less secondary teeth besides third molars, hypodontia), secondarily identified this same MSX1 variant, functioning as a mildly deleterious, moderately penetrant allele. Four of five heterozygous R151S individuals from one Japanese family exhibited the hypodontia phenotype. The in vitro functional assays of the variant protein display partial repression activity with normal nuclear localization. These data establish that the MSX1-R151S allele is a low-frequency, mildly deleterious allele for familial hypodontia that alone is insufficient to cause oral facial clefting. Yet, as this work also establishes its hypomorphic nature, it suggests that it may in fact contribute to the likelihood of common birth disorder phenotypes, such as partial tooth agenesis and oral facial clefting. Nevertheless, the exact mechanism in which differential pleiotropy is manifested will need further and deeper clinical and functional analyses.

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A novel MSX1 mutation in hypodontia

Abstract: MSX1 mutations have been reported in four unrelated families with autosomal dominant tooth agenesis. In one family, some individuals also had cleft lip and/or palate. We have identified a novel MSX1 mutation (559 C --> T, resulting in Gln187Stop) in three individuals of one family.

Cited by 80 publications

References 18 publications

MSX1 mutations and associated disease phenotypes: genotype-phenotype relations

MSX1 mutations and associated disease phenotypes: genotype-phenotype relations

A novel missense mutation in MSX1 underlies autosomal recessive oligodontia with associated dental anomalies in Pakistani families

Clinical and functional data implicate the Arg(151)Ser variant of MSX1 in familial hypodontia

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