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Gene Review

PAX9  -  paired box 9

Homo sapiens

Synonyms: Paired box protein Pax-9
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Disease relevance of PAX9

  • These data suggest that upregulated PAX9 expression is not required for the formation of the majority of squamous cell carcinomas of the human oesophagus [1].
  • PAX9 expression was either lost or significantly reduced in the majority of invasive carcinomas and epithelial dysplasias, the latter representing precancerous lesions [1].
  • Haploinsufficiency of the PAX9 gene might be expected to cause some of the developmental defects and the dysphagia [2].
  • Gain of function of the gene PAX9 on chromosome 14 is a possible candidate for a t(14;18) patient affected with mesomelic bone dysplasia [3].
  • PAX9 and TGFB3 are linked to susceptibility to nonsyndromic cleft lip with or without cleft palate in the Japanese: population-based and family-based candidate gene analyses [4].

High impact information on PAX9

  • Mutation of PAX9 is associated with oligodontia [5].
  • PAX-9 is a novel family member which is closely related in its paired domain to PAX-1 [6].
  • 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, which mainly involves the posterior teeth [7].
  • Natural selection and molecular evolution in primate PAX9 gene, a major determinant of tooth development [7].
  • 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 [8].

Biological context of PAX9

  • In addition, we tested how a missense mutation (T62C) in the paired domain of PAX9 that is responsible for human tooth agenesis (1) affects its functions [9].
  • In humans, mutations in PAX9 are associated with unique phenotypes of familial tooth agenesis that mainly involve posterior teeth [10].
  • 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 [10].
  • The combined defects in DNA binding activities and transactivation function of mutant 219InsGPAX9 likely alter the selective activation and/or repression of PAX9 effector genes during odontogenesis [10].
  • Fluorescence in situ hybridization (FISH) analysis with a cosmid containing the PAX9 gene yielded a signal on only one chromosome 14 homologue and confirmed the presence of a deletion encompassing the PAX9 locus [11].

Anatomical context of PAX9

  • In PAX9, a novel, heterozygous G151A transition in the sequence encoding the paired domain of the PAX9 protein was detected in a patient with agenesis of third molars, second premolars and incisors, but not in her parents, the remaining patients or 162 individuals with normal dentition [12].
  • In a single family with the lack of first and second molars, a mutation in the PAX9 gene was found [13].
  • Notably, the percentage of PAX9-positive cells within the epithelium decreased with increasing malignancy of the epithelial lesion [1].
  • These results identify PAX9 as a sensitive marker for deregulated differentiation of oesophageal keratinocytes and indicate a role for PAX9 in the normal differentiation process of internal stratified squamous epithelia [1].
  • The tooth agenesis phenotype involves all permanent second and third molars and most of the first molars and resembles the earlier reported phenotype that was also associated with a PAX9 mutation [14].

Associations of PAX9 with chemical compounds

  • The A340T transversion creates a stop codon at lysine 114, and truncates the coded PAX9 protein at the end of the DNA-binding paired-box [14].
  • The mutation, 83G-->C, is predicted to result in the substitution of arginine by proline (R28P) in the N-terminal subdomain of PAX9 paired domain [15].
  • 1. Direct sequencing of exons 2 to 4 of PAX9 revealed a cytosine insertion mutation at nucleotide 793, leading to a premature termination of translation at aa 315 [16].
  • Sequencing of the PAX9 gene revealed a missense mutation in the beginning of the paired domain of the molecule, an arginine-to-tryptophan amino-acid change occurring in a position absolutely conserved in all sequenced paired box genes [17].

Physical interactions of PAX9

  • There were statistically significant data suggesting that MSX1 interacts with PAX9 [18].
  • The R28P mutation dramatically reduces DNA binding of the PAX9 paired domain and supports the hypothesis that loss of DNA binding is the pathogenic mechanism by which the mutation causes oligodontia [15].

Other interactions of PAX9

  • No sequence variation was observed in the paired domain of the PAX7 and PAX9 genes [19].
  • Several studies have shown that MSX1 and PAX9 play a role in early tooth development [20].
  • Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9 [21].
  • Novel mutation of the initiation codon of PAX9 causes oligodontia [20].
  • MSX1, PAX9, and TGFA contribute to tooth agenesis in humans [18].

Analytical, diagnostic and therapeutic context of PAX9

  • Direct sequencing and restriction enzyme analysis revealed a novel heterozygous A to G transition mutation in the AUG initiation codon of PAX9 in exon 1 in the affected members of the family [20].
  • In our group of patients with the deficiency of various teeth, in 20% of the patients and their relatives sequence analysis revealed a C-->T transition in the coding sequence of the PAX9 gene [13].
  • Here we report a case of erroneous DS, in which a single nucleotide polymorphism (SNP) in the human PAX9 gene was mistyped due to allele-dependent PCR amplification [22].
  • The latter did not alter the DNA binding activities of wild type Pax9 in gel mobility shift assays [10].


  1. Progressive loss of PAX9 expression correlates with increasing malignancy of dysplastic and cancerous epithelium of the human oesophagus. Gerber, J.K., Richter, T., Kremmer, E., Adamski, J., Höfler, H., Balling, R., Peters, H. J. Pathol. (2002) [Pubmed]
  2. De novo deletion (14)(q11.2q13) including PAX9: clinical and molecular findings. Schuffenhauer, S., Leifheit, H.J., Lichtner, P., Peters, H., Murken, J., Emmerich, P. J. Med. Genet. (1999) [Pubmed]
  3. Defining the breakpoints of proximal chromosome 14q rearrangements in nine patients using flow-sorted chromosomes. Kamnasaran, D., O'Brien, P.C., Schuffenhauer, S., Quarrell, O., Lupski, J.R., Grammatico, P., Ferguson-Smith, M.A., Cox, D.W. Am. J. Med. Genet. (2001) [Pubmed]
  4. PAX9 and TGFB3 are linked to susceptibility to nonsyndromic cleft lip with or without cleft palate in the Japanese: population-based and family-based candidate gene analyses. Ichikawa, E., Watanabe, A., Nakano, Y., Akita, S., Hirano, A., Kinoshita, A., Kondo, S., Kishino, T., Uchiyama, T., Niikawa, N., Yoshiura, K. J. Hum. Genet. (2006) [Pubmed]
  5. Mutation of PAX9 is associated with oligodontia. Stockton, D.W., Das, P., Goldenberg, M., D'Souza, R.N., Patel, P.I. Nat. Genet. (2000) [Pubmed]
  6. Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9. Stapleton, P., Weith, A., Urbánek, P., Kozmik, Z., Busslinger, M. Nat. Genet. (1993) [Pubmed]
  7. Natural selection and molecular evolution in primate PAX9 gene, a major determinant of tooth development. Pereira, T.V., Salzano, F.M., Mostowska, A., Trzeciak, W.H., Ruiz-Linares, A., Chies, J.A., Saavedra, C., Nagamachi, C., Hurtado, A.M., Hill, K., Castro-de-Guerra, D., Silva-Júnior, W.A., Bortolini, M.C. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  8. Reduction of Pax9 gene dosage in an allelic series of mouse mutants causes hypodontia and oligodontia. Kist, R., Watson, M., Wang, X., Cairns, P., Miles, C., Reid, D.J., Peters, H. Hum. Mol. Genet. (2005) [Pubmed]
  9. Functional consequences of interactions between Pax9 and Msx1 genes in normal and abnormal tooth development. Ogawa, T., Kapadia, H., Feng, J.Q., Raghow, R., Peters, H., D'Souza, R.N. J. Biol. Chem. (2006) [Pubmed]
  10. Functional analysis of a mutation in PAX9 associated with familial tooth agenesis in humans. Mensah, J.K., Ogawa, T., Kapadia, H., Cavender, A.C., D'Souza, R.N. J. Biol. Chem. (2004) [Pubmed]
  11. Haploinsufficiency of PAX9 is associated with autosomal dominant hypodontia. Das, P., Stockton, D.W., Bauer, C., Shaffer, L.G., D'Souza, R.N., Wright, T., Patel, P.I. Hum. Genet. (2002) [Pubmed]
  12. Novel mutation in the paired box sequence of PAX9 gene in a sporadic form of oligodontia. Mostowska, A., Kobielak, A., Biedziak, B., Trzeciak, W.H. Eur. J. Oral Sci. (2003) [Pubmed]
  13. The novel polymorphic variants within the paired box of the PAX9 gene are associated with selective tooth agenesis. Kobielak, A., Kobielak, K., Wiśniewski, A.S., Mostowska, A., Biedziak, B., Trzeciak, W.H. Folia Histochem. Cytobiol. (2001) [Pubmed]
  14. Identification of a nonsense mutation in the PAX9 gene in molar oligodontia. Nieminen, P., Arte, S., Tanner, D., Paulin, L., Alaluusua, S., Thesleff, I., Pirinen, S. Eur. J. Hum. Genet. (2001) [Pubmed]
  15. A novel missense mutation in the paired domain of PAX9 causes non-syndromic oligodontia. Jumlongras, D., Lin, J.Y., Chapra, A., Seidman, C.E., Seidman, J.G., Maas, R.L., Olsen, B.R. Hum. Genet. (2004) [Pubmed]
  16. A novel mutation in human PAX9 causes molar oligodontia. Frazier-Bowers, S.A., Guo, D.C., Cavender, A., Xue, L., Evans, B., King, T., Milewicz, D., D'Souza, R.N. J. Dent. Res. (2002) [Pubmed]
  17. A missense mutation in PAX9 in a family with distinct phenotype of oligodontia. Lammi, L., Halonen, K., Pirinen, S., Thesleff, I., Arte, S., Nieminen, P. Eur. J. Hum. Genet. (2003) [Pubmed]
  18. MSX1, PAX9, and TGFA contribute to tooth agenesis in humans. Vieira, A.R., Meira, R., Modesto, A., Murray, J.C. J. Dent. Res. (2004) [Pubmed]
  19. PAX genes and human neural tube defects: an amino acid substitution in PAX1 in a patient with spina bifida. Hol, F.A., Geurds, M.P., Chatkupt, S., Shugart, Y.Y., Balling, R., Schrander-Stumpel, C.T., Johnson, W.G., Hamel, B.C., Mariman, E.C. J. Med. Genet. (1996) [Pubmed]
  20. Novel mutation of the initiation codon of PAX9 causes oligodontia. Klein, M.L., Nieminen, P., Lammi, L., Niebuhr, E., Kreiborg, S. J. Dent. Res. (2005) [Pubmed]
  21. Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. Tan, K., Shaw, A.L., Madsen, B., Jensen, K., Taylor-Papadimitriou, J., Freemont, P.S. J. Biol. Chem. (2003) [Pubmed]
  22. Allele-specific PCR amplification due to sequence identity between a PCR primer and an amplicon: is direct sequencing so reliable? Ikegawa, S., Mabuchi, A., Ogawa, M., Ikeda, T. Hum. Genet. (2002) [Pubmed]
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