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Novel mutations in the IRF6 gene for Van der Woude syndrome


Van der Woude syndrome (VWS, OMIM 119300) is an autosomal dominant craniofacial disorder characterized by pits of the lower lip, hypodontia, and cleft lip and/or cleft palate. It is the most common form of syndromic orofacial clefting and has very high penetrance with varied expressivity. The disease locus for VWS has been mapped to a 1.6-cM region on 1q32–41 between D1S205 and D1S491. Recently, mutations have been found in the interferon regulatory factor 6 (IRF6) gene in patients with VWS and popliteal pterygium syndrome. To identify novel mutations of IRF6 in VWS patients, we screened four Chinese VWS families in all nine exons and their flanking splice junctions by direct sequencing. We identified three missense mutations and one nonsense mutation in IRF6. Our study further confirmed that IRF6 is essential for craniofacial development.

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  1. Brivanlou AH, Darnell JE (2002) Signal transduction and the control of gene expression. Science 295:813–818

  2. Burdick AB (1986) Genetic epidemiology and control of genetic expression in van der Woude syndrome. J Craniofac Genet Dev Biol Suppl 2:99–105

  3. Burdick AB, Bixler D, Puckett CL (1985) Genetic analysis in families with van der Woude syndrome. J Craniofac Genet Dev Biol 5:181–208

  4. Eroshkin A, Mushegian A (1999) Conserved transactivation domain shared by interferon regulatory factors and Smad morphogens. J Mol Med 77:403–405

  5. Hatada S, Kinoshita M, Takahashi S, Nishihara R, Sakumoto H, Fukui A, Noda M, Asashima M (1997) An interferon regulatory factor-related gene (xIRF-6) is expressed in the posterior mesoderm during the early development of Xenopus laevis. Gene 203:183–188

  6. Koillinen H, Wong FK, Rautio J, Ollikainen V, Karsten A, Larson O, Teh BT, Huggare J, Lahermo P, Larsson C, Kere J (2001) Mapping of the second locus for the Van der Woude syndrome to chromosome 1p34. Eur J Hum Genet 9:747–752

  7. Kondo S, Schutte BC, Richardson RJ, Bjork BC, Knight AS, Watanabe Y, Howard E, Lima RL de, Daack-Hirsch S, Sander A, McDonald-McGinn DM, Zackai EH, Lammer EJ, Aylsworth AS, Ardinger HH, Lidral AC, Pober BR, Moreno L, Arcos-Burgos M, Valencia C, Houdayer C, Bahuau M, Moretti-Ferreira D, Richieri-Costa A, Dixon MJ, Murray JC (2002) Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet 32:285–289

  8. Murray JC, Nishimura DY, Buetow KH, Ardinger HH, Spence MA, Sparkes RS, Falk RE, Falk PM, Gardner RJ, Harkness EM, Glinski LP, Pauli RM, Nakamura Y, Green PP, Schinzel A (1990) Linkage of an autosomal dominant clefting syndrome (Van der Woude) to loci on chromosome 1q. Am J Hum Genet 46:486–491

  9. Rintala AE, Ranta R (1981) Lower lip sinuses: I. Epidemiology, microforms and transverse sulci. Br J Plast Surg 34:26–30

  10. Ruan WH, Liu JH, Wu QL (1994) Congenital cleft lip and cleft palate with lower lip pits. Hua Xi Kou Qiang Yi Xue Za Zhi 12:47

  11. Sander A, Moser H, Liechti-Gallati S, Grimm T, Zingg M, Raveh J (1993) Linkage of Van der Woude syndrome (VWS) to REN and exclusion of the candidate gene TGFB2 from the disease locus in a large pedigree. Hum Genet 91:55–62

  12. Sander A, Schmelzle R, Murray J (1994) Evidence for a microdeletion in 1q32–41 involving the gene responsible for Van der Woude syndrome. Hum Mol Genet 3:575–578

  13. Sander A, Murray JC, Scherpbier-Heddema T, Buetow KH, Weissenbach J, Zingg M, Ludwig K, Schmelzle R (1995) Microsatellite-based fine mapping of the Van der Woude syndrome locus to an interval of 4.1 cM between D1S245 and D1S414. Am J Hum Genet 56:310–318

  14. Schutte BC, Sander A, Malik M, Murray JC (1996) Refinement of the Van der Woude gene location and construction of a 3.5-Mb YAC contig and STS map spanning the critical region in 1q32-q41.Genomics 36:507–514

  15. Schutte BC, Bjork BC, Coppage KB, Malik MI, Gregory SG, Scott DJ, Brentzell LM, Watanabe Y, Dixon MJ, Murray JC (2000) A preliminary gene map for the Van der Woude syndrome critical region derived from 900 kb of genomic sequence at 1q32-q41. Genome Res 10:81–94

  16. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N (2001) IRF family of transcription factors as regulators of host defense. Annu Rev Immunol 19:623–655

  17. Zhao M, Xiong B, Guo YG, Liu ZJ, Qi KM, Huang JJ (1994) Congenital lower lip sinuses. Zhong Hua Zheng Xing Shao Shang Wai Ke Za Zhi 10:270–72

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We thank the patients and their families for their participation in this study. We also thank Dr. Ming Zhang, Dr. Kai Tao, Dr. Zeyuan Zhou, and Dr. Chengjin Li, College of Stomatology, Fourth Military Medical University, for recruiting the VWS families and blood collection, and Dr. Jesse Pang and Xujing Wang for comments. This study was supported by the National High Technology "863" Programs of China and the National Science Fund for Distinguished Young Scholars. The authors declare that they have no competing financial interests.

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Correspondence to Landian Hu.

Additional information

X. Wang and J. Liu contributed equally to this work

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Wang, X., Liu, J., Zhang, H. et al. Novel mutations in the IRF6 gene for Van der Woude syndrome. Hum Genet 113, 382–386 (2003).

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  • Cleft Palate
  • Pterygium
  • Cleave Palate
  • Unaffected Family Member
  • Orofacial Cleft