Novel PAX9 and COL1A2 Missense Mutations Causing Tooth Agenesis and OI/DGI without Skeletal Abnormalities (original) (raw)
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Clinical Genetic Basis of Tooth Agenesis
Tooth agenesis is one of the most common congenital malformations in humans. Hypodontia can either occur as an isolated condition (non-syndromic hypodontia) or can be associated with a syndrome (syndromic hypodontia), highlighting the heterogeneity of the condition. Gene anomalies or mutations in MSX1, PAX9, AXIN2 and EDA genes, appear to be most critical during the development of tooth, leading to various forms of tooth agenesis and systemic features. The aim of this paper is to review the genetic basis of hypodontia and identify the genes that have been definitively implicated in the agenesis of human dentition.
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 ...
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.
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.
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 ...
2021
Background: Development of dentition is controlled by numerous genes, proven by experimental animal studies and mutations that have been identified by genetic studies in man. Purpose: In the present study a nonsense mutation has been identified in the PAX9 gene that was associated with molar tooth agenesis (hypodontia or oligodontia). Methodology: The proband of family 1 originally came for treatment to the Department of Pedodontic and Preventive Dentistry. The proband of family 2 was an orthodontic patient of the Department of Orthodontics and Maxillofacial Orthopedics. All family members were clinically examined by one of the authors and agenesis of teeth was also verified with panoramic radiographs. DNA was extracted from venous blood samples using standard methods. The coding region of the PAX9 gene were amplified using four sets of primers Amplification was performed in 100 ml with DNA concentration of 1.5 ng/ml, 1.5 mM MgCl2 and 1 mU polymerase. Results: The A340T transversion...
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.
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.
Genetic basis of dental agenesis - molecular genetics patterning clinical dentistry
Medicina Oral Patología Oral y Cirugia Bucal, 2014
Tooth agenesis is one of the most common congenital malformations in humans. Hypodontia can either occur as an isolated condition (non-syndromic hypodontia) or can be associated with a syndrome (syndromic hypodontia), highlighting the heterogeneity of the condition. Though much progress has been made to identify the developmental basis of tooth formation, knowledge of the etiological basis of inherited tooth loss is still lacking. To date, the mutation spectra of non-syndromic form of familial and sporadic tooth agenesis in humans have revealed defects in various such genes that encode transcription factors, MSX1 and PAX9 or genes that code for a protein involved in canonical Wnt signaling (AXIN2), and a transmembrane receptor of fibroblast growth factors (FGFR1). The aim of this paper is to review the current literature on the molecular mechanisms responsible for selective hypodontia in humans and to present a detailed overview of causative genes and syndromes associated with hypodontia.