Abstract
PAX9 is a paired domain transcription factor that plays a critical role in odontogenesis. All mutations of PAX9 identified to date have been associated with nonsyndromic form of tooth agenesis. The present report describes an unusual novel mutation in PAX9 identified in a family with severe molar oligodontia. This heterozygous deletion combined with 24 bp insertion (including a 5′ splice site) is localized in the second exon beyond the highly conserved paired box sequence, and might result either in a premature termination of translation at aa 210 or in an aberrant splicing, leading to a frameshift and premature termination of translation at aa 314. Real-time PCR analysis revealed no mutated transcript in cultured lymphocytes of one of the affected individuals indicating that the novel mutation might result in rapid degradation of the mutated transcript leading to haploinsufficiency of PAX9. Our results support the view that mutations in PAX9 constitute a causative factor in nonsyndromic oligodontia.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Vastardis H : The genetics of human tooth agenesis: new discoveries for understanding dental anomalies. Am J Orthod Dentofacial Orthop 2000; 117: 650–656.
Schalk-van der Weide Y, Beemer FA, Faber JA, Bosman F : Symptomatology of patients with oligodontia. J Oral Rehabil 1994; 21: 247–261.
Vastardis H, Karimbux N, Guthua SW, Seidman JG, Seidman CE : A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nat Genet 1996; 13: 417–421.
Stockton DW, Das P, Goldenberg M, D'Souza RN, Patel PI : Mutation of PAX9 is associated with oligodontia. Nat Genet 2000; 24: 18–19.
van den Boogaard MJ, Dorland M, Beemer FA, van Amstel HK : MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat Genet 2000; 24: 342–343.
Jumlongras D, Bei M, Stimson JM et al: A nonsense mutation in MSX1 causes Witkop syndrome. Am J Hum Genet 2001; 69: 67–74.
Nieminen P, Arte S, Tanner D et al: Identification of a nonsense mutation in the PAX9 gene in molar oligodontia. Eur J Hum Genet 2001; 9: 743–746.
Das P, Stockton DW, Bauer C et al: Haploinsufficiency of PAX9 is associated with autosomal dominant hypodontia. Hum Genet 2002; 110: 371–376.
Frazier-Bowers SA, Guo DC, Cavender A et al: A novel mutation in human PAX9 causes molar oligodontia. J Dent Res 2002; 81: 129–133.
Lidral AC, Reising BC : The role of MSX1 in human tooth agenesis. J Dent Res 2002; 81: 274–278.
Das P, Hai M, Elcock C et al: Novel missense mutations and a 288-bp exonic insertion in PAX9 in families with autosomal dominant hypodontia. Am J Med Genet 2003; 118: 35–42.
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. Eur J Hum Genet 2003; 11: 866–871.
Mostowska A, Kobielak A, Biedziak B, Trzeciak WH : Novel mutation in the paired box sequence of PAX9 gene in a sporadic form of oligodontia. Eur J Oral Sci 2003; 111: 272–276.
De Muynck S, Schollen E, Matthijs G, Verdonck A, Devriendt K, Carels C : A novel MSX1 mutation in hypodontia. Am J Med Genet 2004; 128: 401–403.
Jumlongras D, Lin JY, Chapra A et al: A novel missense mutation in the paired domain of PAX9 causes non-syndromic oligodontia. Hum Genet 2004; 114: 242–249.
Klein ML, Nieminen P, Lammi L, Niebuhr E, Kreiborg S : Novel mutation of the initiation codon of PAX9 causes oligodontia. J Dent Res 2005; 84: 43–47.
Tucker AS, Al Khamis A, Sharpe PT : Interactions between Bmp-4 and Msx-1 act to restrict gene expression to odontogenic mesenchyme. Dev Dyn 1998; 212: 533–539.
Peters H, Balling R : Teeth. Where and how to make them. Trends Genet 1999; 15: 59–65.
Satokata I, Maas R : Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat Genet 1994; 6: 348–356.
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 1998; 12: 2735–2747.
Hu G, Vastardis H, Bendall AJ et al: Haploinsufficiency of MSX1: a mechanism for selective tooth agenesis. Mol Cell Biol 1998; 18: 6044–6051.
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. J Biol Chem 2004; 279: 5924–5933.
Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F : Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 2002; 22: 1172–1183.
Liu W, Dong X, Mai M et al: Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. Nat Genet 2000; 26: 146–147.
Lammi L, Arte S, Somer M et al: Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet 2004; 74: 1043–1050.
Vieira AR, Meira R, Modesto A, Murray JC : MSX1, PAX9 and TGFA contribute to tooth agenesis in humans. J Dent Res 2004; 83: 723–727.
Lidral AC, Romitti PA, Basart AM et al: Association of MSX1 and TGFβ3 with nonsyndromic clefting in humans. Am J Hum Genet 1998; 63: 557–568.
Zhao JL, Chen YX, Bao L et al: Novel mutations of PAX9 gene in Chinese patients with oligodontia. Zhonghua Kou Qiang Yi Xue Za Zhi 2005; 40: 266–270.
Frischmeyer PA, Dietz HC : Nonsense-mediated mRNA decay in health and disease. Hum Mol Genet 1999; 8: 1893–1900.
Bateman JF, Freddi S, Nattrass G, Savarirayan R : Tissue-specific RNA surveillance? Nonsense-mediated mRNA decay causes collagen X haploinsufficiency in Schmid metaphyseal chondrodysplasia cartilage. Hum Mol Genet 2003; 12: 217–225.
Mostowska A, Kobielak A, Trzeciak WH : Molecular basis of non-syndromic tooth agenesis: mutations of MSX1 and PAX9 reflect their role in patterning human dentition. Eur J Oral Sci 2003; 111: 365–370.
Ogawa T, Kapadia H, Wang B, D'Souza RN : Studies on Pax9–Msx1 protein interactions. Arch Oral Biol 2005; 50: 141–145.
Peres RC, Scarel-Caminaga RM, do Espirito Santo AR, Line SR : Association between PAX-9 promoter polymorphisms and hypodontia in humans. Arch Oral Biol 2005; 50: 861–871.
Acknowledgements
This work was supported by Grant No. P05A 092 26 from the State Committee for Scientific Research (KBN). Editorial assistance of Mr Robert Meehan (M.Sc.) is gratefully acknowledged.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mostowska, A., Biedziak, B. & Trzeciak, W. A novel mutation in PAX9 causes familial form of molar oligodontia. Eur J Hum Genet 14, 173–179 (2006). https://doi.org/10.1038/sj.ejhg.5201536
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5201536
Keywords
This article is cited by
-
Genetic background of nonsyndromic oligodontia: a systematic review and meta-analysis
Journal of Orofacial Orthopedics / Fortschritte der Kieferorthopädie (2013)
-
Familial human hypodontia – is it all in the genes?
British Dental Journal (2007)
-
A novel c.581C>T transition localized in a highly conserved homeobox sequence ofMSX1: is it responsible for oligodontia?
Journal of Applied Genetics (2006)
