title: Spectrum of p63 mutations in a selected patient cohort affected with ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC).
abstract: Heterozygous mutations in the p63 gene underlie a group of at least seven allelic syndromes, including ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC) and Rapp Hodgkin syndrome (RHS), which involves varying degrees of ectodermal dysplasia, orofacial clefting and limb malformations. Mutations in the AEC and Rapp Hodgkin syndromes cluster in the 3' end of the p63 gene. Previously reported mutations are mainly missense and frameshift mutations in exons 13 and 14, affecting the p63alpha-specific SAM (sterile alpha motif) and TI (transactivation inhibitory) domains. A patient cohort affected by AEC syndrome was evaluated during International Research Symposium supported by the National Foundation for Ectodermal Dysplasias. Nineteen patients underwent full clinical evaluations and 18 had findings consistent with a diagnosis of AEC syndrome. These 19 patients, along with 5 additional relatives had genomic DNA analysis. Twenty-one of the 24 participants from 12 families were found to have mutations in the p63 gene. Eleven different mutations were identified; 10 were novel mutations. Eight were missense mutations within the coding region of the SAM domain. Three other mutations were located in exon 14 sequences, which encode the TI domain. The effects of the mutations in the SAM and TI domains are poorly understood and functional studies are required to understand the pathological mechanisms. However, AEC and RHS mutations in the 5' and 3' ends of the p63 gene point towards a critical role of the DeltaNp63alpha isoform for the AEC/RHS phenotype.
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands.
authors.forename: Tuula
authors.initials: T
authors.lastname: Rinne
authors.forename: Emine
authors.initials: E
authors.lastname: Bolat
authors.forename: Rowdy
authors.initials: R
authors.lastname: Meijer
authors.forename: Hans
authors.initials: H
authors.lastname: Scheffer
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D002971:Cleft Lip / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D002972:Cleft Palate / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004476:Ectodermal Dysplasia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005091:Exons / Q000235:genetics; D005143:Eyelids / Q000002:abnormalities*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics; D000076106:SAM Domain and HD Domain-Containing Protein 1; D016415:Sequence Alignment; D013577:Syndrome; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D004247:DNA; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins