title: Gain-of-function mutation in ADULT syndrome reveals the presence of a second transactivation domain in p63.
abstract: The transcriptional co-activator p63 is of crucial importance for correct development of the limbs, ectodermal appendages (skin, nails, teeth, hair, glands), lip and palate. Mutations in the p63 gene are found in a number of human syndromes, including ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) syndrome, limb-mammary syndrome (LMS), Hay-Wells syndrome and in non-syndromic split-hand/split-foot malformation (SHFM). Each syndrome has a specific pattern of mutations with different functional effects in in vitro functional assays. We report a mutation R298Q in acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome, another EEC-like condition. The mutation is located in the DNA binding domain of p63, which harbors almost all EEC associated mutations. However, unlike mutations in EEC syndrome, the R298Q ADULT syndrome mutation does not impair DNA binding. Rather, the mutation confers novel transcription activation capacity on the DeltaN-p63gamma isoform, which normally does not possess such activity. These results confirm that ADULT syndrome is a clinically as well as molecularly distinct member of the expanding p63 mutation family of human malformation syndromes. Our results further show that p63 contains a second transactivation domain which is normally repressed and can become activated by mutations in the DNA binding domain of p63.
authors.affiliation: Department of Human Genetics 417, University Medical Centre Nijmegen, Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Pascal H G
authors.initials: PH
authors.lastname: Duijf
authors.forename: Kaate R J
authors.initials: KR
authors.lastname: Vanmolkot
authors.forename: Peter
authors.initials: P
authors.lastname: Propping
authors.forename: Waltraut
authors.initials: W
authors.lastname: Friedl
authors.forename: Elmar
authors.initials: E
authors.lastname: Krieger
authors.forename: Frank
authors.initials: F
authors.lastname: McKeon
authors.forename: Volker
authors.initials: V
authors.lastname: Dötsch
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006801:Humans; D008565:Membrane Proteins; D008958:Models, Molecular; D020125:Mutation, Missense; D010750:Phosphoproteins / Q000235:genetics*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000235:genetics; D013577:Syndrome; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins
chemical_list: C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins