title: Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.
abstract: EEC syndrome is an autosomal dominant disorder characterized by ectrodactyly, ectodermal dysplasia, and facial clefts. We have mapped the genetic defect in several EEC syndrome families to a region of chromosome 3q27 previously implicated in the EEC-like disorder, limb mammary syndrome (LMS). Analysis of the p63 gene, a homolog of p53 located in the critical LMS/EEC interval, revealed heterozygous mutations in nine unrelated EEC families. Eight mutations result in amino acid substitutions that are predicted to abolish the DNA binding capacity of p63. The ninth is a frameshift mutation that affects the p63alpha, but not p63beta and p63gamma isotypes. Transactivation studies with these mutant p63 isotypes provide a molecular explanation for the dominant character of p63 mutations in EEC syndrome.
authors.affiliation: Department of Human Genetics 417, University Hospital Nijmegen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Celli
authors.forename: P
authors.initials: P
authors.lastname: Duijf
authors.forename: B C
authors.initials: BC
authors.lastname: Hamel
authors.forename: M
authors.initials: M
authors.lastname: Bamshad
authors.forename: B
authors.initials: B
authors.lastname: Kramer
authors.forename: A P
authors.initials: AP
authors.lastname: Smits
authors.forename: R
authors.initials: R
authors.lastname: Newbury-Ecob
authors.forename: R C
authors.initials: RC
authors.lastname: Hennekam
authors.forename: G
authors.initials: G
authors.lastname: Van Buggenhout
authors.forename: A
authors.initials: A
authors.lastname: van Haeringen
authors.forename: C G
authors.initials: CG
authors.lastname: Woods
authors.forename: A J
authors.initials: AJ
authors.lastname: van Essen
authors.forename: R
authors.initials: R
authors.lastname: de Waal
authors.forename: G
authors.initials: G
authors.lastname: Vriend
authors.forename: D A
authors.initials: DA
authors.lastname: Haber
authors.forename: A
authors.initials: A
authors.lastname: Yang
authors.forename: F
authors.initials: F
authors.lastname: McKeon
authors.forename: H G
authors.initials: HG
authors.lastname: Brunner
authors.forename: H
authors.initials: H
authors.lastname: van Bokhoven
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D004268:DNA-Binding Proteins; D004476:Ectodermal Dysplasia / Q000235:genetics; D005145:Face / Q000002:abnormalities; D005260:Female; D005532:Foot Deformities, Congenital / Q000235:genetics; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D005819:Genetic Markers; D018095:Germ-Line Mutation; D006228:Hand Deformities, Congenital / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics*; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
chemical_list: C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D008565:Membrane Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins