Alternative titles; symbols
HGNC Approved Gene Symbol: PAX9
Cytogenetic location: 14q13.3 Genomic coordinates (GRCh38): 14:36,657,568-36,679,362 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q13.3 | Tooth agenesis, selective, 3 | 604625 | Autosomal dominant | 3 |
Stapleton et al. (1993) isolated a cosmid for PAX9, a novel member of the paired box-containing gene family. They found it to be closely related in its paired domain to PAX1 (167411). Wallin et al. (1993) independently cloned the Pax9 gene in the mouse. From a study of the DNA sequence encoding the highly conserved paired domain, they also concluded that the gene is a member of the same subgroup as Pax1/undulated.
Wang et al. (2009) stated that PAX9 contains 341 amino acids and is composed of an N-terminal paired DNA-binding domain, an octapeptide motif, and a C-terminal transcriptional regulatory domain, which is rich in alanine, serine, proline, and glycine residues.
As a first step toward identifying cis-regulatory elements of PAX9 by means of comparative genomics, Santagati et al. (2001) analyzed genome regions encompassing the PAX9 gene in humans, mice, and Japanese pufferfish (Fugu rubripes). They demonstrated that both the genomic organization of the Pax9 gene and its physical association with Nkx2.9 are conserved in the 3 species. In the human, NKX2.8 (603245) is located about 80 kb upstream of PAX9. PAX9 and NKX2.8 are oriented head to head. By sequence comparison, Santagati et al. (2001) found that Nkx2.9 is most similar to human NKX2.8, and stated that the 2 genes are orthologous. Santagati et al. (2001) found a novel upstream exon and putative transcription start sites in mouse Pax9. They suggested that transcription of Pax9 may be initiated at 2 alternative start sites and driven by TATA-less promoters.
By analysis of somatic cell hybrids and by FISH analysis Stapleton et al. (1993) demonstrated that the PAX9 gene is located on chromosome 14q12-q13.
By the segregation of markers in an interspecific backcross, Wallin et al. (1993) mapped the mouse Pax9 gene to the proximal part of chromosome 12. They predicted that the homologous gene in the human might be on either chromosome 2 or chromosome 14 because of the 2 regions of syntenic homology displayed by mouse chromosome 12 in its proximal portion.
By genomewide analysis of a family segregating autosomal dominant selective tooth agenesis (STHAG3; 604625), Stockton et al. (2000) identified a frameshift mutation within the paired domain of PAX9 (167416.0001). Affected members had oligodontia. All had normal primary dentition but lacked most permanent molars. Some of those affected also lacked maxillary and/or mandibular second premolars, as well as mandibular central incisors. Stockton et al. (2000) first performed a genomewide search using microsatellite markers and identified a critical region that included the PAX9 gene on chromosome 14. Mutation analysis of the coding regions of exons 2-4 of PAX9 demonstrated an insertion of a G at nucleotide 219, resulting in frameshift. Relative to the finding of other abnormalities in Pax9-knockout mice, Stockton et al. (2000) noted that affected members of this family showed no limb anomalies and no evidence for calcium metabolism abnormalities or compromised immune system.
In 3 families with selective tooth agenesis described as hypodontia primarily involving molars, Das et al. (2003) performed molecular analysis and identified 2 novel mutation mechanisms. Linkage analysis of 2 large families showed that the hypodontia was linked to the PAX9 locus, and a missense mutation in the PAX9 gene was identified in each family (K91E, 167416.0004; L21P, 167416.0005). In a pair of identical twins with hypodontia in the third family, Das et al. (2003) identified a 288-bp insertion within exon 2 of PAX9, resulting in a putative frameshift mutation and a premature stop codon (167416.0006).
Lammi et al. (2003) analyzed the PAX9 gene in 3 generations of a Finnish family segregating an autosomal dominant oligodontia phenotype and identified a novel arg26-to-trp (R26W) mutation (167416.0008) in a highly conserved domain of the molecule. The authors noted that a mutation of the homologous arginine of PAX6 has been shown to affect the target DNA specificity of that gene, and suggested that a similar mechanism may explain the distinct oligodontia phenotypes.
Zhao et al. (2005) investigated the mutational characteristics of the PAX9 gene in Chinese patients with autosomal dominant oligodontia from 4 unrelated families. Sequence analysis revealed heterozygosity for a novel frameshift mutation (167416.0014) and a novel missense mutation (167416.0015) in 2 families. Zhao et al. (2005) suggested that the mutant PAX9 protein acquires functional defects in DNA binding, as well as loss of function of PAX9 resulting in haploinsufficiency during the patterning of the dentition and the subsequent tooth agenesis.
In affected members of a family segregating molar oligodontia, Kapadia et al. (2006) identified heterozygosity for a missense mutation within the paired domain of the PAX9 gene (I87F; 167416.0009). Functional studies demonstrated that the mutant protein lacked DNA-binding activity but did not interfere with the DNA binding of the wildtype. Kapadia et al. (2006) suggested that a loss-of-function mechanism contributed to haploinsufficiency of PAX9 in this family.
Wang et al. (2009) determined the structural and functional consequences of PAX9 paired domain missense mutations and correlated findings with the associated dental phenotype variations. All mutant PAX9 proteins were localized in the nucleus of transfected cells and physically interacted with MSX1 (142983) protein. The K91E (167416.0004) and G51S (167416.0013) mutants retained the ability to bind the consensus paired domain recognition sequence; the others (L21P, R28P, R26W, and I87F) were unable or only partly able to interact with this DNA fragment and also showed a similarly impaired capability for activation of transcription from the MSX1 and BMP4 (112262) promoters. Wang et al. (2009) noted that the degree of loss of DNA-binding activity and promoter activation correlated well with the severity of the tooth agenesis pattern seen in vivo.
Peters et al. (1998) generated Pax9-deficient mice and showed that PAX9 is essential for the development of a variety of organs and skeletal elements. Homozygous Pax9 mutant mice died shortly after birth, most likely as a consequence of a cleft secondary palate. Homozygous knockout mice lacked a thymus, parathyroid glands, and ultimobranchial bodies, organs which are derived from the pharyngeal pouches. In all limbs, a supernumerary preaxial digit was formed, but the flexor of the hindlimb toes was missing. Furthermore, craniofacial and visceral skeletogenesis was disturbed, and all teeth were absent. In Pax9-deficient embryos, tooth development was arrested at the bud stage. At that stage, Pax9 is required for the mesenchymal expression of Bmp4, Msx1, and Lef1, suggesting a role for Pax9 in the establishment of the inductive capacity of the tooth mesenchyme.
Kist et al. (2005) described a hypomorphic Pax9 allele, which they termed Pax9-neo, producing decreased levels of Pax9 wildtype mRNA and showed that this caused oligodontia in mice. Homozygous Pax9 neo/neo mice exhibited hypoplastic or missing lower incisors and third molars. When combined with a Pax9 null allele, the Pax9 neo/null compound mutants developed severe forms of oligodontia. The missing molars were arrested at different developmental stages and posterior molars were consistently arrested at an earlier stage, suggesting that a reduction of Pax9 gene dosage may affect the dental field as a whole. Pax9 neo/neo and neo/null mice also showed defects in enamel formation of the continuously growing incisors, whereas molars exhibited increased attrition and reparative dentin formation.
In a large family in which members of 4 generations were known to have oligodontia (STHAG3; 604625) in an autosomal dominant pedigree pattern, Stockton et al. (2000) identified a frameshift mutation, 219insG, in the PAX9 gene, predicted to result truncated peptide lacking the second DNA-binding domain. By immunofluorescence analysis, Mensah et al. (2004) showed that the 291insG mutation resulted in defective nuclear localization with intense cytoplasmic but negative nuclear fluorescence.
Nieminen et al. (2001) identified an A-to-T transversion at nucleotide 340 in exon 2 of the PAX9 gene in 3 affected members of a Finnish family with autosomal dominant oligodontia (STHAG3; 604625). The mutation created a stop codon at lys114 and truncated the protein at the end of the DNA-binding paired box. The affected individuals lacked all second and third permanent molars as well as both maxillary lateral incisors. The proband and his mother also lacked all first permanent molars and several second premolars. In the primary dentition of the proband, all second molars were missing. In addition, some permanent teeth appeared smaller than normal in affected individuals. The authors suggested haploinsufficiency as a likely effect of the mutation.
Das et al. (2002) demonstrated deletion of the PAX9 gene in a father and daughter with severe hypodontia (STHAG3; 604625), involving agenesis of all primary and permanent molars. Hemizygosity at the PAX9 locus was initially discovered in the 2 affected individuals when an informative single nucleotide polymorphism (SNP), identified while sequencing the PAX9 gene for mutations, appeared to demonstrate nonmendelian inheritance. FISH analysis with a cosmid containing the PAX9 gene yielded a signal on only one chromosome 14 homolog and confirmed the presence of a deletion encompassing the PAX9 locus. They estimated that the size of the deletion was between 44 and 100 kb. This observation suggests that oligodontia and hypodontia are not fundamentally different, or at least can be caused by different mutations in the same gene.
In a family in which autosomal dominant hypodontia (STHAG3; 604625) principally involving molars occurred in at least 3 generations, Das et al. (2003) identified a 271A-G transition in exon 2 of the PAX9 gene, resulting in a lys91-to-glu (K91E) mutation, in affected individuals. By in vitro DNA binding assay, Wang et al. (2009) showed that the K91E mutation resulted in only mildly affected DNA binding.
In a large kindred in which autosomal dominant hypodontia (STHAG3; 604625) principally involving molars occurred in at least 5 generations, Das et al. (2003) identified a 62T-C transition in exon 2 of the PAX9 gene, resulting in a leu21-to-pro (L21P) mutation, in affected members; the mutation segregated with the disorder. By in vitro DNA binding assay, Wang et al. (2009) showed that the L21P mutation resulted in total abrogation of DNA binding.
In a pair of identical twins with molar hypodontia (STHAG3; 604625), Das et al. (2003) identified a 288-bp insertion within exon 2 of the PAX9 gene that resulted in a putative frameshift and a premature stop codon. The insertion was associated with a loss of 7 bp from exon 2. A block of 256 bp of sequence within the insertion was completely identical to downstream sequence from the second intron of the PAX9 gene.
Jumlongras et al. (2004) described a heterozygous 83G-C transversion in the PAX9 gene, resulting in an arg28-to-pro (R28P) mutation in affected members of a family with autosomal dominant nonsyndromic oligodontia (STHAG3; 604625). They analyzed the binding of wildtype and mutant PAX9 paired domain to double-stranded DNA targets. The R28P mutation dramatically reduced DNA binding and supported the conclusion that loss of DNA binding is the pathogenic mechanism by which the mutation causes oligodontia.
Lammi et al. (2003) analyzed 3 generations of a Finnish family segregating autosomal dominant oligodontia (STHAG3; 604625) and identified a 76C-T transition in the PAX9 gene, resulting in an arg26-to-trp (R26W) substitution at the start of the highly conserved paired domain of the molecule. Affected family members had a distinct phenotype involving missing premolars, canines, and incisors in addition to permanent molars, as well as reduced size of both deciduous and permanent teeth. By in vitro DNA binding assay, Wang et al. (2009) showed that the R26W mutation resulted in total abrogation of DNA binding.
In affected members of a family segregating molar oligodontia (STHAG3; 604625), Kapadia et al. (2006) identified heterozygosity for a 259A-T transversion in exon 2 of the PAX9 gene, resulting in the substitution of phenylalanine for a highly conserved isoleucine at residue 87 (I87F) within C-terminal subdomain of the paired domain of the protein. By in vitro DNA binding assay, Wang et al. (2009) showed that the I87F mutation resulted in severely diminished DNA binding, but detectable binding upon longer exposures.
In affected members of a large family segregating autosomal dominant molar oligodontia (STHAG3; 604625), Frazier-Bowers et al. (2002) identified heterozygosity for insertion of a cytosine at nucleotide 793 in exon 4 of the PAX9 gene, leading to premature termination of translation at amino acid 315.
In affected members of a Chinese family segregating autosomal dominant oligodontia (STHAG3; 604625), Klein et al. (2005) identified heterozygosity for an A-to-G transition in the AUG initiation codon of PAX9. The phenotype in this family was severe in terms of missing teeth; e.g., the proband lacked all permanent molars, all second premolars, and upper first premolars, in combination with hypodontia in the primary dentition. Klein et al. (2005) noted that the phenotype most closely resembled that in the family reported by Das et al. (2002) with a PAX9 deletion (167416.0003).
In affected members of a family segregating autosomal dominant oligodontia (STHAG3; 604625), Mostowska et al. (2006) identified heterozygosity for a 3-bp deletion combined with a 24-bp insertion (including a 5-prime splice site) in exon 2 of the PAX9 gene, beyond the highly conserved paired box sequence. The mutation might result in a premature termination of translation at amino acid 210 or in aberrant splicing leading to a frameshift and premature termination of translation at amino acid 314. Mostowska et al. (2006) proposed that the mutation might result in rapid degradation of the mutated transcript, leading to haploinsufficiency. The proband and 4 other affected individuals had an identical pattern of missing teeth, i.e., all lacked 18 permanent teeth, including molars, second premolars, and lower first incisors, and all had normal primary dentition. The mutation was not found in unaffected family members or in 150 unrelated control individuals.
In a woman who presented with agenesis of second premolars and several incisors (STHAG3; 604625), Mostowska et al. (2003) identified heterozygosity for a de novo PAX9 mutation, a 151G-A transition in exon 2, resulting in a gly51-to-ser (G51S) substitution in the paired domain of the protein. The mutation was not found in the parents, who had normal dentition, or in 162 healthy, unrelated individuals. By in vitro DNA binding assay, Wang et al. (2009) showed that the G51S mutation resulted in only mildly affected DNA binding. Reporter assays showed equal or increased transcriptional activation of BMP4 (112262) and MSX1 (142983) compared to wildtype protein, and the G51S mutant showed diminished activation upon coexpression with wildtype protein.
In affected members of a Chinese family segregating autosomal dominant oligodontia (STHAG3; 604625), Zhao et al. (2005) identified heterozygosity for a 1-bp insertion in exon 2 of the PAX9 gene (190insG).
In affected members of a Chinese family segregating autosomal dominant oligodontia (STHAG3; 604625), Zhao et al. (2005) identified heterozygosity for a 139C-T transition in exon 2 of the PAX9 gene, resulting in an arg47-to-trp (R47W) substitution in a conserved region of the N-terminal subdomain of the paired domain involved in DNA contact. Zhao et al. (2007) described a 16-year-old female proband who was missing 20 permanent teeth, including 9 molars, 4 maxillary premolars, 3 canines, and all central incisors. Some teeth showed abnormal crown and root shapes. In vitro functional expression studies indicated that the mutant protein had reduced DNA binding, suggesting haploinsufficiency.
Das, P., Hai, M., Elcock, C., Leal, S. M., Brown, D. T., Brook, A. H., Patel, P. I. Novel missense mutations and a 288-bp exonic insertion in PAX9 in families with autosomal dominant hypodontia. Am. J. Med. Genet. 118A: 35-42, 2003. [PubMed: 12605438] [Full Text: https://doi.org/10.1002/ajmg.a.10011]
Das, P., Stockton, D. W., Bauer, C., Shaffer, L. G., D'Souza, R. N., Wright, J. T., Patel, P. I. Haploinsufficiency of PAX9 is associated with autosomal dominant hypodontia. Hum. Genet. 110: 371-376, 2002. [PubMed: 11941488] [Full Text: https://doi.org/10.1007/s00439-002-0699-1]
Frazier-Bowers, S. A., Guo, D. C., Cavender, A., Xue, L., Evans, B., King, T., Milewicz, D., D'Souza, R. N. A novel mutation in human PAX9 causes molar oligodontia. J. Dent. Res. 81: 129-133, 2002. [PubMed: 11827258]
Jumlongras, D., Lin, J.-Y., Chapra, A., Seidman, C. E., Seidman, J. G., Maas, R. L., Olsen, B. R. A novel missense mutation in the paired domain of PAX9 causes non-syndromic oligodontia. Hum. Genet. 114: 242-249, 2004. [PubMed: 14689302] [Full Text: https://doi.org/10.1007/s00439-003-1066-6]
Kapadia, H., Frazier-Bowers, S., Ogawa, T., D'Souza, R. N. Molecular characterization of a novel PAX9 missense mutation causing posterior tooth agenesis. Europ. J. Hum. Genet. 14: 403-409, 2006. [PubMed: 16479262] [Full Text: https://doi.org/10.1038/sj.ejhg.5201574]
Kist, R., Watson, M., Wang, X., Cairns, P., Miles, C., Reid, D. J., Peters, H. Reduction of Pax9 gene dosage in an allelic series of mouse mutants causes hypodontia and oligodontia. Hum. Molec. Genet. 14: 3605-3617, 2005. [PubMed: 16236760] [Full Text: https://doi.org/10.1093/hmg/ddi388]
Klein, M. L., Nieminen, P., Lammi, L., Niebuhr, E., Kreiborg, S. Novel mutation of the initiation codon of PAX9 causes oligodontia. J. Dent. Res. 84: 43-47, 2005. [PubMed: 15615874] [Full Text: https://doi.org/10.1177/154405910508400107]
Lammi, L., Halonen, K., Pirinen, S., Thesleff, I., Arte, S., Nieminen, P. A missense mutation in PAX9 in a family with distinct phenotype of oligodontia. Europ. J. Hum. Genet. 11: 866-871, 2003. [PubMed: 14571272] [Full Text: https://doi.org/10.1038/sj.ejhg.5201060]
Mensah, J. K., Ogawa, T., Kapadia, H., Cavender, A. C., D'Souza, R. N. Functional analysis of a mutation in PAX9 associated with familial tooth agenesis in humans. J. Biol. Chem. 279: 5924-5933, 2004. [PubMed: 14607846] [Full Text: https://doi.org/10.1074/jbc.M305648200]
Mostowska, A., Biedziak, B., Trzeciak, W. H. A novel mutation in PAX9 causes familial form of molar oligodontia. Europ. J. Hum. Genet. 14: 173-179, 2006. [PubMed: 16333316] [Full Text: https://doi.org/10.1038/sj.ejhg.5201536]
Mostowska, A., Kobielak, A., Biedziak, B., Trzeciak, W. H. Novel mutation in the paired box sequence of PAX9 gene in a sporadic form of oligodontia. Europ. J. Oral Sci. 111: 272-276, 2003. [PubMed: 12786960] [Full Text: https://doi.org/10.1034/j.1600-0722.2003.00036.x]
Nieminen, P., Arte, S., Tanner, D., Paulin, L., Alaluusua, S., Thesleff, I., Pirinen, S. Identification of a nonsense mutation in the PAX9 gene in molar oligodontia. Europ. J. Hum. Genet. 9: 743-746, 2001. [PubMed: 11781684] [Full Text: https://doi.org/10.1038/sj.ejhg.5200715]
Peters, H., Neubuser, A., Kratochwil, K., Balling, R. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev. 12: 2735-2747, 1998. [PubMed: 9732271] [Full Text: https://doi.org/10.1101/gad.12.17.2735]
Santagati, F., Gerber, J.-K., Blusch, J. H., Kokubu, C., Peters, H., Adamski, J., Werner, T., Balling, R., Imai, K. Comparative analysis of the genomic organization of Pax9 and its conserved physical association with Nkx2-9 in the human, mouse, and pufferfish genomes. Mammalian Genome 12: 232-237, 2001. [PubMed: 11252173] [Full Text: https://doi.org/10.1007/s003350010267]
Stapleton, P., Weith, A., Urbanek, P., Kozmik, Z., Busslinger, M. Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9. Nature Genet. 3: 292-298, 1993. [PubMed: 7981748] [Full Text: https://doi.org/10.1038/ng0493-292]
Stockton, D. W., Das, P., Goldenberg, M., D'Souza, R. N., Patel, P. I. Mutation of PAX9 is associated with oligodontia. (Letter) Nature Genet. 24: 18-19, 2000. [PubMed: 10615120] [Full Text: https://doi.org/10.1038/71634]
Wallin, J., Mizutani, Y., Imai, K., Miyashita, N., Moriwaki, K., Taniguchi, M., Koseki, H., Balling, R. A new Pax gene, Pax-9, maps to mouse chromosome 12. Mammalian Genome 4: 354-358, 1993. [PubMed: 8358169] [Full Text: https://doi.org/10.1007/BF00360584]
Wang, Y., Groppe, J. C., Wu, J., Ogawa, T., Mues, G., D'Souza, R. N., Kapadia, H. Pathogenic mechanisms of tooth agenesis linked to paired domain mutations in human PAX9. Hum. Molec. Genet. 18: 2863-2874, 2009. [PubMed: 19429910] [Full Text: https://doi.org/10.1093/hmg/ddp221]
Zhao, J., Chen, Y., Bao, L., Xia, Q., Wu, T., Zhou, L. Novel mutations of PAX9 gene in Chinese patients with oligodontia. Chinese J. Stomat. 40: 266-270, 2005. [PubMed: 16191360]
Zhao, J., Hu, Q., Chen, Y., Luo, S., Bao, L., Xu, Y. A novel missense mutation in the paired domain of human PAX9 causes oligodontia. Am. J. Med. Genet. 143A: 2592-2597, 2007. [PubMed: 17910065] [Full Text: https://doi.org/10.1002/ajmg.a.31993]