Identification of a novel mutation in the PAX9 gene in a family affected by oligodontia and other dental anomalies (original) (raw)
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A novel nonsense mutation in PAX9 is associated with marked variability in number of missing teeth
European Journal of Oral Sciences, 2007
Non-syndromic congenital absence (agenesis) of one or more permanent teeth (excluding the third molar) occurs in more than 8% of the Danish population (1, 2). In most cases, one or two second premolars or lateral maxillary incisors are missing, whereas agenesis of canines and first molars is rare. Agenesis of six or more permanent teeth (oligodontia) is extremely rare (0.16%) (1) compared with agenesis of one to five permanent teeth, excluding the third molars (hypodontia, OMIM #167416). Mutations associated with non-syndromic hypodontia and oligodontia are known to occur in the genes PAX9, MSX1, and AXIN2 (3-17). Non-syndromic congenital absence of missing teeth is generally inherited in an autosomal-dominant manner, and only one case of autosomal-recessive inheritance is known for an MSX1 missense mutation (18). Pathogenetic mutations have been identified in relatively few of the studied families with non-syndromic absence of permanent teeth, as reported by Gerits et al. (19), who analyzed eight families with severe oligodontia without finding any mutations in MSX1, PAX9 or AXIN2, and by who analyzed two families with oligodontia without identifying pathogenetic mutations in PAX9. These observations are in agreement with our own observations after sequencing PAX9 and MSX1 from nine families with oligodontia. Presumably, several disease genes causing non-syndromic agenesis of permanent teeth have not yet been identified.
PAX9 and MSX1 transcription factor genes in non-syndromic dental agenesis
Archives of Oral …, 2011
Objective: The molecular variation of paired domain box gene 9 (PAX9) was previously investigated by our research group and a high degree of evolutionary conservation in coding and non-coding regions was observed except in exon 3. PAX9 is a transcription factor important in tooth development, and we wanted to verify its role in dental agenesis in detail. Since dental development is a complex trait we also decided to examine the influence of another transcription factor, muscle segment homeodomain-homeobox 1 (MSX1) on it. Design: A total of 360 consecutively ascertained patients seeking orthodontic treatment were screened for tooth agenesis and 33% of them were found to have it. Thirty-five of those with agenesis and 15 controls had their DNA studied for PAX9 exons 2, 3, 4 and adjacent regions (total of 1476 base pairs, bp) as well as MSX1 exon 2 (698 bp). A trio (a proband and her parents) was also studied. Results: Six polymorphic sites were found, three in PAX9 exon 3 and three in MSX1 exon2. MSX1 rs1095 derived allele occurred in individuals with agenesis only, and two other mutations in this gene had been earlier associated with tooth agenesis. Homozygosity for the PAX9 Ala240Pro mutation was studied in a family (proband and her parents), suggesting recessive inheritance with variable expressivity for the dental agenesis found. Conclusion: Common variants located out of the DNA binding domain of the two PAX9 and MSX1 genes can also be related to tooth agenesis.
Functional Analysis of a Mutation in PAX9 Associated with Familial Tooth Agenesis in Humans
Journal of Biological Chemistry, 2003
Pax9 is a paired domain-containing transcription factor that plays an essential role in the patterning of murine dentition. In humans, mutations in PAX9 are associated with unique phenotypes of familial tooth agenesis that mainly involve posterior teeth. Among these, a frameshift mutation (219InsG) within the paired domain of PAX9 produces a protein product associated with a severe form of molar agenesis in a single family. The objectives of this study were to gain new insights into the molecular pathogenesis of the 219InsG mutation and its role in tooth agenesis. Here we describe functional defects in DNA binding and transactivation of mutant 219InsGPax9. Although wild type Pax9 binds to the high affinity paired domain recognition sequences, e5 and CD19 -2(A-ins), the 219InsGPax9 mutant protein was unable to bind to these cognate DNA-binding sites. In co-transfection assays, wild type Pax9 activated reporter gene transcription although the mutant was transcriptionally inactive. Immunolocalization data show that Pax9 and 219InsGPax9 proteins are synthesized in mammalian cells but that the nuclear localization of the mutant Pax9 protein is altered. Furthermore, transactivation by the full-length Pax9 protein from paired domain binding sites was not impaired by the 219InsGPax9 mutant. The latter did not alter the DNA binding activities of wild type Pax9 in gel mobility shift assays. The combined defects in DNA binding activities and transactivation function of mutant 219InsG-PAX9 likely alter the selective activation and/or repression of PAX9 effector genes during odontogenesis. This loss-of-function of PAX9 most likely results in its haploinsufficiency during the patterning of dentition and the subsequent loss of posterior teeth.
Nine Novel PAX9 Mutations and a Distinct Tooth Agenesis Genotype-Phenotype
Journal of Dental Research
Tooth agenesis is one of the most common developmental anomalies affecting function and esthetics. The paired-domain transcription factor, Pax9, is critical for patterning and morphogenesis of tooth and taste buds. Mutations of PAX9 have been identified in patients with tooth agenesis. Despite significant progress in the genetics of tooth agenesis, many gaps in knowledge exist in refining the genotype-phenotype correlation between PAX9 and tooth agenesis. In the present study, we complete genetic and phenotypic characterization of multiplex Chinese families with nonsyndromic (NS) tooth agenesis. Direct sequencing of polymerase chain reaction products revealed 9 novel (c.140G>C, c.167T>A, c.332G>C, c.194C>A, c.271A>T, c.146delC, c.185_189dup, c.256_262dup, and c.592delG) and 2 known heterozygous mutations in the PAX9 gene among 120 probands. Subsequently, pedigrees were extended, and we confirmed that the mutations co-segregated with the tooth agenesis phenotype (with ...
Human Molecular Genetics, 2005
Missing teeth (hypodontia and oligodontia) are a common developmental abnormality in humans and heterozygous mutations of PAX9 have recently been shown to underlie a number of familial, non-syndromic cases. Whereas PAX9 haploinsufficiency has been suggested as the underlying genetic mechanism, it is not known how this affects tooth development. Here we describe a novel, hypomorphic Pax9 mutant allele (Pax9 neo ) producing decreased levels of Pax9 wild-type mRNA and show that this causes oligodontia in mice. Homozygous Pax9 neo mutants (Pax9 neo/neo ) exhibit hypoplastic or missing lower incisors and third molars, and when combined with the null allele Pax9 lacZ , the compound mutants (Pax9 neo/lacZ ) develop severe forms of oligodontia. The missing molars are arrested at different developmental stages and posterior molars are consistently arrested at an earlier stage, suggesting that a reduction of Pax9 gene dosage affects the dental field as a whole. In addition, hypomorphic Pax9 mutants show defects in enamel formation of the continuously growing incisors, whereas molars exhibit increased attrition and reparative dentin formation. Together, we conclude that changes of Pax9 expression levels have a direct consequence for mammalian dental patterning and that a minimal Pax9 gene dosage is required for normal morphogenesis and differentiation throughout tooth development.
Tooth agenesis patterns and variants in PAX9: A systematic review
Japanese Dental Science Review, 2023
Mutations in PAX9 are the most common genetic cause of tooth agenesis (TA). The aim of this study was to systematically review the profiles of the TA and PAX9 variants and establish their genotype-phenotype correlation. Forty articles were eligible for 178 patients and 61 mutations (26 in frame and 32 null mutations). PAX9 mutations predominantly affected molars, mostly the second molar, and the mandibular first premolar was the least affected. More missing teeth were found in the maxilla than the mandible, and with null mutations than in-frame mutations. The number of missing teeth was correlated with the locations of the in-frame mutations with the C-terminus mutations demonstrating the fewest missing teeth. The null mutation location did not influence the number of missing teeth. Null mutations in all locations predominantly affected molars. For the in-frame mutations, a missing second molar was commonly associated with mutations in the highly conserved paired DNA-binding domain, particularly the linking peptide (100% prevalence). In contrast, C-terminus mutations were rarely associated with missing second molars and anterior teeth, but were commonly related to an absent second premolar. These finding indicate that the mutation type and position contribute to different degrees of loss of PAX9 function that further differentially influences the manifestations of TA. This study provides novel information on the correlation of the PAX9 genotype-phenotype, aiding in the genetic counseling for TA.
Molecular characterization of a novel PAX9 missense mutation causing posterior tooth agenesis
European Journal of Human Genetics, 2006
Autosomal dominant mutations in the gene encoding the paired box containing transcription factor PAX9 are associated with nonsyndromic human tooth agenesis that primarily affect posterior dentition. The molecular mechanisms contributing to its pathogenesis are poorly understood. In this study, we describe a novel mutation in PAX9 in a family with molar oligodontia. This heterozygous mutation results in the substitution of a highly conserved isoleucine residue by phenylalanine within the carboxyl-terminal subdomain of the paired domain. Immunolocalization and cell fractionation studies to ascertain the subcellular localization of the Ile87Phe protein showed that both wild-type and mutant proteins are synthesized in mammalian cells and that the mutation does not alter the nuclear localization of the mutant protein. Gel-shift assays using two cognate paired-domain recognition sequences, e5 and CD19-2(A-ins), revealed that while wild-type Pax9 binds to both sequences, the mutant protein was unable to bind these sites. In addition, the latter did not alter the DNA-binding activities of wild-type Pax9. Furthermore, we evaluated the ability of the Ile87Phe mutant protein to form a complex with a partner protein, Msx1, and found that the mutation under study has no effect on this interaction. Based on our observed defects in DNA binding by the mutant protein, we propose a loss-of-function mechanism that contributes to haploinsufficiency of PAX9 in this family with posterior tooth agenesis.
2022
Congenital tooth agenesis (CTA) is one of the most common craniofacial anomalies. Its frequency varies among different population depending upon the genetic heterogeneity. CTA could be of familial or sporadic and syndromic or non-syndromic. Five major genes are found to be associated with non-syndromic CTA namely, PAX9, MSX1, EDA1, AXIN2 and WNT10A. In this study, an India family with CTA was investigated and a novel c.336C>G variation was identified in the exon 3 of PAX9, leading to substitution of evolutionary conserved Cys with Trp at 112 amino acid position located at the functionally significant DNA binding paired domain region. Functional analysis revealed that p.Cys112Trp mutation did not prevent the nuclear localization although mutant protein had higher cytoplasmic retention. EMSA using e5 probe revealed that mutant protein was unable to bind with the paired-domain binding site. Subsequently, GST pull-down assay revealed lower binding activity of the mutant protein with ...
The role of Msx1 and Pax9 in pathogenetic mechanisms of tooth agenesis
Dental Journal (Majalah Kedokteran Gigi), 2009
Background: Tooth agenesis is one of the most common developmental anomalies in human, which one or a few teeth are absent because they have never formed, may cause cosmetic or occlusal harm, while severe agenesis which are relatively rare require clinical , may cause cosmetic or occlusal harm, while severe agenesis which are relatively rare require clinical attention to support and maintain the dental function. Molecular studies have demonstrated that tooth development is under strict genetic control. Purpose: This article want to review the genetic regulating that are responsible for tooth agenesis especially the role of Msx1 and Pax9 in pathogenetic mechanisms of tooth agenesis. review: Tooth agenesis is a consequence of a qualitatively or quantitatively ooth agenesis is a consequence of a qualitatively or quantitatively impaired function of genetic networks, which regulate tooth development. Mutations in Msx1 and Pax9 genes are dominant for tooth agenesis in humans. The Pax9 gene, which codes for a paired domain-containing transcription factor that plays an essential role in the development of mammal dentition, has been associated with selective tooth agenesis in humans and mice. Conclusion: Reduced amount of functional Msx1 or Pax9 protein in the tooth forming cells is able to cause severe and selective tooth agenesis. There are differences in the frequency of agenesis of specific teeth associated with the defects in Msx1 and defects in Pax9.
Neuro endocrinology letters, 2015
Tooth agenesis is one of the most common developmental anomalies in humans. Genetic and environmental factors may be of etiological importance in this condition. Among genes involved in tooth morphogenesis, mutations in PAX9, MSX1, AXIN2, WNT10a, and EDA genes have been associated with tooth agenesis. The aim of our study was to investigate the relationship between the PAX9 gene variants and tooth agenesis in the Czech population. The selected regions of the PAX9 gene were analysed by direct sequencing and compared with the reference sequence from the GenBank online database (NCBI). We found several novel variants in the PAX9 gene, e.g. insertion g.5100_5101insC (rs11373281) with simultaneous substitution g.5272C>G (rs4904155) in exon 1, and mutation g.10934C>T (Gly203Gly, rs61754301) in exon 3. In subjects with full dentition we observed polymorphisms g.10276A>G (rs12882923) and g.10289A>G (rs12883049) in IVS2 (intervening sequence 2) previously related to tooth agenesi...