Human Molecular Genetics, 2001, Vol. 10, No. 3 221-229
© 2001 Oxford University Press
Hay–Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63
1Department of Cell and Molecular Pathology, St John’s Institute of Dermatology, The Guy’s, King’s College and St Thomas’ Hospitals’ Medical School, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK, 2Department of Human Genetics 417 and 3Department of Pathology, University Medical Centre Nijmegen, Box 9101, 6500 HB Nijmegen, The Netherlands, 4Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA, 5Department of Pharmaceutical Chemistry, University of California, Box 0446, S1234, San Francisco, CA, USA, 6Department of Dermatology, The Hospital for Sick Children, Great Ormond Street, London WC1N3JH, UK, 7Department of Dermatology, NYU School of Medicine, 560 First Avenue, Room H-100, New York, NY 10016, USA, 8Department of Clinical Genetics, Leiden University Medical Centre, Albinusdreef 2, 2333 SA Leiden, The Netherlands, 9Department of Medical Genetics, UMC Utrecht, Box 85090, 3508 AB Utrecht, The Netherlands and 10Department of Pediatrics, University of Utah Health Sciences Center, and Shriners Hospitals for Children, Intermountain unit, 15 North 2030 East, Salt Lake City, UT 84112, USA
Hay–Wells syndrome, also known as ankyloblepharon–ectodermal dysplasia-clefting (AEC) syndrome (OMIM 106260), is a rare autosomal dominant disorder characterized by congenital ectodermal dysplasia, including alopecia, scalp infections, dystrophic nails, hypodontia, ankyloblepharon and cleft lip and/or cleft palate. This constellation of clinical signs is unique, but some overlap can be recognized with other ectodermal dysplasia syndromes, for example ectrodactyly–ectodermal dysplasia–cleft lip/palate (EEC; OMIM 604292), limb–mammary syndrome (LMS; OMIM 603543), acro-dermato-ungual-lacrimal-tooth syndrome (ADULT; OMIM 103285) and recessive cleft lip/palate–ectodermal dysplasia (CLPED1; OMIM 225060). We have recently demonstrated that heterozygous mutations in the p63 gene are the major cause of EEC syndrome. Linkage studies suggest that the related LMS and ADULT syndromes are also caused by mutations in the p63 gene. Thus, it appears that p63 gene mutations have highly pleiotropic effects. We have analysed p63 in AEC syndrome patients and identified missense mutations in eight families. All mutations give rise to amino acid substitutions in the sterile alpha motif (SAM) domain, and are predicted to affect protein–protein interactions. In contrast, the vast majority of the mutations found in EEC syndrome are amino acid substitutions in the DNA-binding domain. Thus, a clear genotype–phenotype correlation can be recognized for EEC and AEC syndromes.
+ To whom correspondence should be addressed. Tel: +31 24 3614017; Fax: +31 24 3540488; Email: h.vanbokhoven@antrg.azn.nl
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