PAX9 explained

Paired box gene 9, also known as PAX9, is a protein which in humans is encoded by the PAX9 gene.^{[1] [2]} It is also found in other mammals.^[3]

Expression and function

This gene is a member of the paired box (PAX) family of transcription factors. During mouse embryogenesis Pax9 expression starts from embryonic day 8.5 and becomes more evident by E9.5; at this stage its expression is restricted to the pharyngeal endoderm.^{[4] [5]} Later on, Pax9 is also expressed in the axial skeleton. Pax9 is required for craniofacial, tooth and limb development,^[3] and may more generally involve development of stratified squamous epithelia as well as various organs and skeletal elements.^[1] PAX9 plays a role in the absence of wisdom teeth in some human populations (possibly along with the less well studied AXIN2 and MSX1).^[3]

Clinical significance

This gene was found amplified in lung cancer. The amplification covers three tissue developmental genes - TTF1, NKX2-8, and PAX9.^[6] It appears that certain lung cancer cells select for DNA copy number amplification and increased RNA/protein expression of these three coamplified genes for functional advantages.

Oligodontia

Oligodontia is a genetic disorder caused by the mutation of the PAX9 gene. This disorder results in the congenital absence of 6 or more permanent teeth, with the exception of the third molar.^[7] Also known as selective tooth agenesis (STHAG), it is the most common disorder in regard to human dentition, affecting a little less than one fourth of the population. The gene PAX9 which can be found on chromosome 14 encodes a group of transcription factors that play an important role in early tooth development.^[8] In humans, a frameshift mutation in the paired domain of PAX9 was discovered in those affected with oligodontia.^[9] Multiple mechanisms are possible by which the mutation may arise. Recently, a study involving the missense mutation of a PAX9 gene suggests that the loss of function due to the absence DNA binding domain is a mechanism that causes oligodontia.^[10] Those who express the PAX9 mutation and develop the disorder continue to have a normal life expectancy. Along with the mutation of the PAX9 gene, MSX1 gene mutations have also shown to affect dental development in fetuses.

Interactions

PAX9 has been shown to interact with JARID1B.^[11]

Further reading

• Kobielak A, Kobielak K, Wiśniewski AS, Mostowska A, Biedziak B, Trzeciak WH . The novel polymorphic variants within the paired box of the PAX9 gene are associated with selective tooth agenesis . Folia Histochemica et Cytobiologica . 39 . 2 . 111–2 . 2001 . 11374781 .
• Bannykh SI, Emery SC, Gerber JK, Jones KL, Benirschke K, Masliah E . Aberrant Pax1 and Pax9 expression in Jarcho-Levin syndrome: report of two Caucasian siblings and literature review . American Journal of Medical Genetics. Part A . 120A . 2 . 241–6 . July 2003 . 12833407 . 10.1002/ajmg.a.20192 . 1145497 .
• Peters H, Schuster G, Neubüser A, Richter T, Höfler H, Balling R . Isolation of the Pax9 cDNA from adult human esophagus . Mammalian Genome . 8 . 1 . 62–4 . January 1997 . 9021154 . 10.1007/s003359900351 . 26099337 .
• Stockton DW, Das P, Goldenberg M, D'Souza RN, Patel PI . Mutation of PAX9 is associated with oligodontia . Nature Genetics . 24 . 1 . 18–9 . January 2000 . 10615120 . 10.1038/71634 . 27526349 .
• Hetzer-Egger C, Schorpp M, Boehm T . Evolutionary conservation of gene structures of the Pax1/9 gene family . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1492 . 2–3 . 517–21 . July 2000 . 10899593 . 10.1016/s0167-4781(00)00130-5 .
• 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 . European Journal of Human Genetics . 9 . 10 . 743–6 . October 2001 . 11781684 . 10.1038/sj.ejhg.5200715 . free .
• Das P, Stockton DW, Bauer C, Shaffer LG, D'Souza RN, Wright T, Patel PI . Haploinsufficiency of PAX9 is associated with autosomal dominant hypodontia . Human Genetics . 110 . 4 . 371–6 . April 2002 . 11941488 . 10.1007/s00439-002-0699-1 . 8452 .
• Ikegawa S, Mabuchi A, Ogawa M, Ikeda T . Allele-specific PCR amplification due to sequence identity between a PCR primer and an amplicon: is direct sequencing so reliable? . Human Genetics . 110 . 6 . 606–8 . June 2002 . 12107448 . 10.1007/s00439-002-0735-1 . 34993937 .
• Gerber JK, Richter T, Kremmer E, Adamski J, Höfler H, Balling R, Peters H . Progressive loss of PAX9 expression correlates with increasing malignancy of dysplastic and cancerous epithelium of the human oesophagus . The Journal of Pathology . 197 . 3 . 293–7 . July 2002 . 12115874 . 10.1002/path.1115 . 36999418 .
• Peck S, Peck L, Kataja M . Concomitant occurrence of canine malposition and tooth agenesis: evidence of orofacial genetic fields . American Journal of Orthodontics and Dentofacial Orthopedics . 122 . 6 . 657–60 . December 2002 . 12490878 . 10.1067/mod.2002.129915 .
• Mostowska A, Kobielak A, Biedziak B, Trzeciak WH . Novel mutation in the paired box sequence of PAX9 gene in a sporadic form of oligodontia . European Journal of Oral Sciences . 111 . 3 . 272–6 . June 2003 . 12786960 . 10.1034/j.1600-0722.2003.00036.x .
• 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 . European Journal of Human Genetics . 11 . 11 . 866–71 . November 2003 . 14571272 . 10.1038/sj.ejhg.5201060 . free .
• Mensah JK, Ogawa T, Kapadia H, Cavender AC, D'Souza RN . Functional analysis of a mutation in PAX9 associated with familial tooth agenesis in humans . The Journal of Biological Chemistry . 279 . 7 . 5924–33 . February 2004 . 14607846 . 10.1074/jbc.M305648200 . free .

Notes and References

1. Web site: Entrez Gene: PAX9 paired box gene 9.
2. Stapleton P, Weith A, Urbánek P, Kozmik Z, Busslinger M . Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9 . Nature Genetics . 3 . 4 . 292–8 . April 1993 . 7981748 . 10.1038/ng0493-292 . 21338655 .
3. Pereira TV, Salzano FM, Mostowska A, Trzeciak WH, Ruiz-Linares A, Chies JA, Saavedra C, Nagamachi C, Hurtado AM, Hill K, Castro-de-Guerra D, Silva-Júnior WA, Bortolini MC . Natural selection and molecular evolution in primate PAX9 gene, a major determinant of tooth development . Proceedings of the National Academy of Sciences of the United States of America . 103 . 15 . 5676–81 . April 2006 . 16585527 . 1458632 . 10.1073/pnas.0509562103 . 2006PNAS..103.5676P . free .
4. Peters H, Neubüser A, Kratochwil K, Balling R . Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities . Genes & Development . 12 . 17 . 2735–47 . September 1998 . 9732271 . 317134 . 10.1101/gad.12.17.2735 .
5. Neubüser A, Koseki H, Balling R . Characterization and developmental expression of Pax9, a paired-box-containing gene related to Pax1 . Developmental Biology . 170 . 2 . 701–16 . August 1995 . 7649395 . 10.1006/dbio.1995.1248 . free .
6. Kendall J, Liu Q, Bakleh A, Krasnitz A, Nguyen KC, Lakshmi B, Gerald WL, Powers S, Mu D . Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer . Proceedings of the National Academy of Sciences of the United States of America . 104 . 42 . 16663–8 . October 2007 . 17925434 . 2034240 . 10.1073/pnas.0708286104 . 2007PNAS..10416663K . free .
7. Stockton DW, Das P, Goldenberg M, D'Souza RN, Patel PI . Mutation of PAX9 is associated with oligodontia . Nature Genetics . 24 . 1 . 18–9 . January 2000 . 10615120 . 10.1038/71634 . 27526349 .
8. Chi N, Epstein JA . Getting your Pax straight: Pax proteins in development and disease . Trends in Genetics . 18 . 1 . 41–7 . January 2002 . 11750700 . 10.1016/s0168-9525(01)02594-x.
9. Klein ML, Nieminen P, Lammi L, Niebuhr E, Kreiborg S . Novel mutation of the initiation codon of PAX9 causes oligodontia . Journal of Dental Research . 84 . 1 . 43–7 . January 2005 . 15615874 . 10.1177/154405910508400107 . 31928079 .
10. Jumlongras D, Lin JY, Chapra A, Seidman CE, Seidman JG, Maas RL, Olsen BR . A novel missense mutation in the paired domain of PAX9 causes non-syndromic oligodontia . Human Genetics . 114 . 3 . 242–9 . February 2004 . 14689302 . 10.1007/s00439-003-1066-6 . 12537564 .
11. Tan K, Shaw AL, Madsen B, Jensen K, Taylor-Papadimitriou J, Freemont PS . Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9 . The Journal of Biological Chemistry . 278 . 23 . 20507–13 . June 2003 . 12657635 . 10.1074/jbc.M301994200 . free .