Molecular characterization of a novel PAX9 missense mutation causing posterior tooth agenesis

Kapadia, Hitesh; Frazier‐Bowers, Sylvia A.; Ogawa, Takuya; D’Souza, Rena N.

doi:10.1038/sj.ejhg.5201574

Cited by 61 publications

(46 citation statements)

References 20 publications

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“…This is supported by experimental evidence showing that the mutated protein is unable to bind to known target DNA sequences or to activate transcription (Hu et al, '98;Jumlongras et al, 2004;Mensah et al, 2004;Kapadia et al, 2006). All stop codon-creating defects in exon 1 of MSX1 and exon 2 of PAX9 may render the mRNA carrying the mutation susceptible to degradation by the nonsensemediated decay mechanism, but this has been experimentally shown only for the mutation affecting the exon 2-intron 2 junction of PAX9 Fig.…”

Section: Msx1 and Pax9 In Tooth Agenesismentioning

confidence: 90%

Genetic basis of tooth agenesis

Nieminen¹

2009

J Exp Zool Pt B

230

215

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Tooth agenesis or hypodontia, failure to develop all normally developing teeth, is one of the most common developmental anomalies in man. Common forms, including third molar agenesis and hypodontia of one or more of the incisors and premolars, constitute the great majority of cases. They typically affect those teeth that develop latest in each tooth class and these teeth are also most commonly affected in more severe and rare types of tooth agenesis. Specific vulnerability of the last developing teeth suggests that agenesis reflects quantitative defects during dental development. So far molecular genetics has revealed the genetic background of only rare forms of tooth agenesis. Mutations in MSX1, PAX9, AXIN2 and EDA have been identified in familial severe agenesis (oligodontia) and mutations in many other genes have been identified in syndromes in which tooth agenesis is a regular feature. Heterozygous loss of function mutations in many genes reduce the gene dose, whereas e.g. in hypohidrotic ectodermal dysplasia (EDA) the complete inactivation of the partially redundant signaling pathway reduces the signaling centers. Although these mechanisms involve quantitative disturbances, the phenotypes associated with mutations in different genes indicate that in addition to an overall reduction of odontogenic potential, tooth class-specific and more complex mechanisms are also involved. Although several of the genes so far identified in rare forms of tooth agenesis are being studied as candidate genes of common third molar agenesis and incisor and premolar hypodontia, it is plausible that novel genes that contribute to these phenotypes will also become identified.

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Section: Msx1 and Pax9 In Tooth Agenesismentioning

confidence: 90%

Genetic basis of tooth agenesis

Nieminen¹

2009

J Exp Zool Pt B

230

215

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“…While MSX1 mutations have been reported to involve cleft lip and palate [van den Boogaard et al, 2000] and Witkop syndrome [Jumlongras et al, 2001], along with missing teeth, all known PAX9 mutations are associated with nonsyndromic oligodontia that can involve all types of permanent teeth, especially molars. Collectively, these data suggest that PAX9 plays a dominant role in the development of posterior teeth [Stockton et al, 2000;Nieminen et al, 2001;Das et al, 2002;Frazier-Bowers et al, 2002;Das et al, 2003;Lammi et al, 2003;Mostowska et al, 2003;Jumlongras et al, 2004;Klein et al, 2005;Zhao et al, 2005;Kapadia et al, 2006;Mostowska et al, 2006;Tallón-Walton et al, 2007].…”

mentioning

confidence: 99%

Identification and Functional Analysis of Two Novel <i>PAX9</i> Mutations

Wang¹,

Wu²,

Wu³

et al. 2008

Cells Tissues Organs

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The paired-domain transcription factor PAX9 plays a critical role in tooth development, as heterozygous mutations in PAX9 have been shown to be associated with human tooth agenesis. In this study, we report 2 novel missense mutations, gly6arg (G6R) and ser43lys (S43K), in the paired domain of PAX9 in Chinese patients with varying degrees of nonsyndromic tooth agenesis. Excluding third molars, the individual with the G6R mutation was missing 2 mandibular incisors and a maxillary premolar, while the phenotype of individuals with the S43K mutation consisted of peg-shaped upper lateral incisors and missing molars, premolars and canines. As these 2 mutations occur at highly conserved amino acids in the PAX gene family and between different species, we further analyzed the effects of the mutations on the function of the resulting proteins. Immunofluorescence and immunoblotting studies showed that the mutations did not alter nuclear localization in mammalian cells. Gel shift and super shift assays indicate that both mutant proteins bound DNA at a lower level than the normal protein, with G6R having a greater affinity for DNA than S43K. Likewise, the G6R protein was able to transcriptionally activate a Bmp4 promoter construct to a greater extent than S43K. Our finding that the severity of tooth agenesis in the patients was correlated to the DNA-binding capacity of the mutated PAX9 9proteins supports the hypothesis that DNA binding is responsible for the genetic defect.

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“…[29][30][31][32] Although the MSX proteins generally function as transcriptional repressors, these effects may be modulated by protein-protein interactions. Notably, the Msx1 protein has seven ancient, highly conserved sequence motifs, named Msx homology (MH) domains, 1 which likely modulate its interactions with several other binding partners, including Pax9.…”

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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Molecular characterization of a novel PAX9 missense mutation causing posterior tooth agenesis

Cited by 61 publications

References 20 publications

Genetic basis of tooth agenesis

Genetic basis of tooth agenesis

Identification and Functional Analysis of Two Novel <i>PAX9</i> Mutations

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

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