Search tips
Search criteria 


Logo of jmedgeneJournal of Medical GeneticsVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
J Med Genet. 2002 August; 39(8): 559–566.
PMCID: PMC1735218

Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts


EEC syndrome is an autosomal dominant disorder with the cardinal signs of ectrodactyly, ectodermal dysplasia, and orofacial clefts. EEC syndrome has been linked to chromosome 3q27 and heterozygous p63 mutations were detected in unrelated EEC families. In addition, homozygous p63 null mice exhibit craniofacial abnormalities, limb truncations, and absence of epidermal appendages, such as hair follicles and tooth primordia. In this study, we screened 39 syndromic patients, including four with EEC syndrome, five with syndromes closely related to EEC syndrome, and 30 with other syndromic orofacial clefts and/or limb anomalies. We identified heterozygous p63 mutations in three unrelated cases of EEC syndrome, two Iowa white families and one sporadic case in a Filipino boy. One family is atypical for EEC and has features consistent with Hay-Wells syndrome. In this family, the mutation ablates a splice acceptor site and, in the other two, mutations produce amino acid substitutions, R280C and R304Q, which alter conserved DNA binding sites. Germline mosaicism was detected in the founder of the mutation in one case. These three cases show significant interfamilial and intrafamilial variability in expressivity. We also screened p63 in 62 patients with non-syndromic orofacial clefts, identifying an intronic single nucleotide polymorphism but finding no evidence of mutations that would explain even a subset of non-syndromic orofacial clefts. This study supports a common role for p63 in classical EEC syndrome, both familial and sporadic, but not in other related or non-syndromic forms of orofacial clefts.

Full Text

The Full Text of this article is available as a PDF (420K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Schutte BC, Murray JC. The many faces and factors of orofacial clefts. Hum Mol Genet. 1999;8(10):1853–1859. [PubMed]
  • Jones MC. Etiology of facial clefts: prospective evaluation of 428 patients. Cleft Palate J. 1988 Jan;25(1):16–20. [PubMed]
  • Wyszynski DF, Beaty TH, Maestri NE. Genetics of nonsyndromic oral clefts revisited. Cleft Palate Craniofac J. 1996 Sep;33(5):406–417. [PubMed]
  • Schutte BC, Sander A, Malik M, Murray JC. 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. 1996 Sep 15;36(3):507–514. [PubMed]
  • Stanier P, Forbes SA, Arnason A, Bjornsson A, Sveinbjornsdottir E, Williamson R, Moore G. The localization of a gene causing X-linked cleft palate and ankyloglossia (CPX) in an Icelandic kindred is between DXS326 and DXYS1X. Genomics. 1993 Sep;17(3):549–555. [PubMed]
  • Braybrook C, Doudney K, Marçano AC, Arnason A, Bjornsson A, Patton MA, Goodfellow PJ, Moore GE, Stanier P. The T-box transcription factor gene TBX22 is mutated in X-linked cleft palate and ankyloglossia. Nat Genet. 2001 Oct;29(2):179–183. [PubMed]
  • Celli J, Duijf P, Hamel BC, Bamshad M, Kramer B, Smits AP, Newbury-Ecob R, Hennekam RC, Van Buggenhout G, van Haeringen A, et al. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell. 1999 Oct 15;99(2):143–153. [PubMed]
  • Ianakiev P, Kilpatrick MW, Toudjarska I, Basel D, Beighton P, Tsipouras P. Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27. Am J Hum Genet. 2000 Jul;67(1):59–66. [PubMed]
  • McGrath JA, Duijf PH, Doetsch V, Irvine AD, de Waal R, Vanmolkot KR, Wessagowit V, Kelly A, Atherton DJ, Griffiths WA, et al. Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63. Hum Mol Genet. 2001 Feb 1;10(3):221–229. [PubMed]
  • Roelfsema NM, Cobben JM. The EEC syndrome: a literature study. Clin Dysmorphol. 1996 Apr;5(2):115–127. [PubMed]
  • Fryns JP, Legius E, Dereymaeker AM, Van den Berghe H. EEC syndrome without ectrodactyly: report of two new families. J Med Genet. 1990 Mar;27(3):165–168. [PMC free article] [PubMed]
  • Hasegawa T, Hasegawa Y, Asamura S, Nagai T, Tsuchiya Y, Ninomiya M, Fukushima Y. EEC syndrome (ectrodactyly, ectodermal dysplasia and cleft lip/palate) with a balanced reciprocal translocation between 7q11.21 and 9p12 (or 7p11.2 and 9q12) in three generations. Clin Genet. 1991 Sep;40(3):202–206. [PubMed]
  • Qumsiyeh MB. EEC syndrome (ectrodactyly, ectodermal dysplasia and cleft lip/palate) is on 7p11.2-q21.3. Clin Genet. 1992 Aug;42(2):101–101. [PubMed]
  • Fukushima Y, Ohashi H, Hasegawa T. The breakpoints of the EEC syndrome (ectrodactyly, ectodermal dysplasia and cleft lip/palate) confirmed to 7q11.21 and 9p12 by fluorescence in situ hybridization. Clin Genet. 1993 Jul;44(1):50–50. [PubMed]
  • Scherer SW, Poorkaj P, Massa H, Soder S, Allen T, Nunes M, Geshuri D, Wong E, Belloni E, Little S, et al. Physical mapping of the split hand/split foot locus on chromosome 7 and implication in syndromic ectrodactyly. Hum Mol Genet. 1994 Aug;3(8):1345–1354. [PubMed]
  • Maas SM, de Jong TP, Buss P, Hennekam RC. EEC syndrome and genitourinary anomalies: an update. Am J Med Genet. 1996 Jun 14;63(3):472–478. [PubMed]
  • van Bokhoven H, Hamel BC, Bamshad M, Sangiorgi E, Gurrieri F, Duijf PH, Vanmolkot KR, van Beusekom E, van Beersum SE, Celli J, et al. p63 Gene mutations in eec syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. Am J Hum Genet. 2001 Sep;69(3):481–492. [PubMed]
  • Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dötsch V, Andrews NC, Caput D, McKeon F. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell. 1998 Sep;2(3):305–316. [PubMed]
  • Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature. 1999 Apr 22;398(6729):708–713. [PubMed]
  • Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, Tabin C, Sharpe A, Caput D, Crum C, et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature. 1999 Apr 22;398(6729):714–718. [PubMed]
  • Guion-Almeida ML, Rodini ES, Pereira SC, Richieri-Costa A. Amniotic bands and the EEC syndrome. Birth Defects Orig Artic Ser. 1996;30(1):171–177. [PubMed]
  • Romitti PA, Lidral AC, Munger RG, Daack-Hirsch S, Burns TL, Murray JC. Candidate genes for nonsyndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: evaluation of genotype-environment interactions from a population-based case-control study of orofacial clefts. Teratology. 1999 Jan;59(1):39–50. [PubMed]
  • Romitti PA, Munger RG, Murray JC, Daack-Hirsch S, Hanson JW, Burns TL. The effect of follow-up on limiting non-participation bias in genetic epidemiologic investigations. Eur J Epidemiol. 1998 Feb;14(2):129–138. [PubMed]
  • Murray JC, Daack-Hirsch S, Buetow KH, Munger R, Espina L, Paglinawan N, Villanueva E, Rary J, Magee K, Magee W. Clinical and epidemiologic studies of cleft lip and palate in the Philippines. Cleft Palate Craniofac J. 1997 Jan;34(1):7–10. [PubMed]
  • Hagiwara K, McMenamin MG, Miura K, Harris CC. Mutational analysis of the p63/p73L/p51/p40/CUSP/KET gene in human cancer cell lines using intronic primers. Cancer Res. 1999 Sep 1;59(17):4165–4169. [PubMed]
  • Semina EV, Reiter R, Leysens NJ, Alward WL, Small KW, Datson NA, Siegel-Bartelt J, Bierke-Nelson D, Bitoun P, Zabel BU, et al. Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet. 1996 Dec;14(4):392–399. [PubMed]
  • Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. [PubMed]
  • Cho Y, Gorina S, Jeffrey PD, Pavletich NP. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science. 1994 Jul 15;265(5170):346–355. [PubMed]
  • Hainaut P, Hernandez T, Robinson A, Rodriguez-Tome P, Flores T, Hollstein M, Harris CC, Montesano R. IARC Database of p53 gene mutations in human tumors and cell lines: updated compilation, revised formats and new visualisation tools. Nucleic Acids Res. 1998 Jan 1;26(1):205–213. [PMC free article] [PubMed]
  • Mount SM. A catalogue of splice junction sequences. Nucleic Acids Res. 1982 Jan 22;10(2):459–472. [PMC free article] [PubMed]
  • Reed R, Maniatis T. Intron sequences involved in lariat formation during pre-mRNA splicing. Cell. 1985 May;41(1):95–105. [PubMed]
  • Padgett RA, Grabowski PJ, Konarska MM, Seiler S, Sharp PA. Splicing of messenger RNA precursors. Annu Rev Biochem. 1986;55:1119–1150. [PubMed]
  • Broman KW, Murray JC, Sheffield VC, White RL, Weber JL. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet. 1998 Sep;63(3):861–869. [PubMed]
  • Ory K, Legros Y, Auguin C, Soussi T. Analysis of the most representative tumour-derived p53 mutants reveals that changes in protein conformation are not correlated with loss of transactivation or inhibition of cell proliferation. EMBO J. 1994 Aug 1;13(15):3496–3504. [PubMed]
  • Forrester K, Lupold SE, Ott VL, Chay CH, Band V, Wang XW, Harris CC. Effects of p53 mutants on wild-type p53-mediated transactivation are cell type dependent. Oncogene. 1995 Jun 1;10(11):2103–2111. [PubMed]
  • Rolley N, Butcher S, Milner J. Specific DNA binding by different classes of human p53 mutants. Oncogene. 1995 Aug 17;11(4):763–770. [PubMed]
  • Küster W, Majewski F, Meinecke P. EEC syndrome without ectrodactyly? Report of 8 cases. Clin Genet. 1985 Aug;28(2):130–135. [PubMed]
  • FRASER FC. Thoughts on the etiology of clefts of the palate and lip. Acta Genet Stat Med. 1955;5(4):358–369. [PubMed]
  • Fraser FC. The genetics of cleft lip and cleft palate. Am J Hum Genet. 1970 May;22(3):336–352. [PubMed]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group