"Eight of the mutations reported here (p.Phe526Leu, p.Ile537Thr, p.Asp544Tyr, p.Asp544Val, p.Leu545Pro, p.Pro551- Leu, p.Gly561Asp and p.Gly561Val) are missense mutations within the coding region of the SAM domain (Fig. 1). Such mutations are characteristic for AEC/RHS, since 57% (16 out of 28) of the known AEC/RHS mutations create amino acid substitutions in the SAM domain [McGrath et al., 2001; van Bokhoven and Brunner, 2002; Kantaputra et al., 2003; Tsutsui et al., 2003; Bertola et al., 2004; Shotelersuk et al., 2005; Payne et al., 2005; Sorasio et al., 2006; Rinne et al., 2007]. However, two of these missense mutations (p.Asp544Tyr, p.Asp544Val) are flanking the intron 13–exon 14 boundary and may cause a splice site defect of exon 14. "
[Show abstract][Hide abstract] 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.
American Journal of Medical Genetics Part A 09/2009; 149A(9):1948-51. DOI:10.1002/ajmg.a.32793 · 2.05 Impact Factor
"Ectodermal dysplasias caused by TP63 mutations share many manifestations, however, only patients with AEC or RHS exhibit skin fragility, resulting in the formation of erosive skin lesions [Cambiaghi et al., 1994;Siegfried et al., 2005]. In addition to this overlap in clinical symptoms, AEC and RHS are caused by mutations in the same region of the TP63 gene, and identical mutations can give rise to either AEC or RHS [Bertola et al., 2004;Rinne et al., 2007;Sorasio et al., 2006]. Since both the genetic defect and the clinical findings of AEC and RHS overlap, these disorders are now thought to represent the same condition and will be referred to as AEC in this paper. "
[Show abstract][Hide abstract] ABSTRACT: Dominant mutations in TP63 cause ankyloblepharon ectodermal dysplasia and clefting (AEC), an ectodermal dysplasia characterized by skin fragility. Since DeltaNp63alpha is the predominantly expressed TP63 isoform in postnatal skin, we hypothesized that mutant DeltaNp63alpha proteins are primarily responsible for skin fragility in AEC patients. We found that mutant DeltaNp63alpha proteins expressed in AEC patients function as dominant-negative molecules, suggesting that the human AEC skin phenotype could be mimicked in mouse skin by downregulating DeltaNp63alpha. Indeed, downregulating DeltaNp63 expression in mouse epidermis caused severe skin erosions, which resembled lesions that develop in AEC patients. In both cases, lesions were characterized by suprabasal epidermal proliferation, delayed terminal differentiation, and basement membrane abnormalities. By failing to provide structural stability to the epidermis, these defects likely contribute to the observed skin fragility. The development of a mouse model for AEC will allow us to further unravel the genetic pathways that are normally regulated by DeltaNp63 and that may be perturbed in AEC patients. Ultimately, these studies will not only contribute to our understanding of the molecular mechanisms that cause skin fragility in AEC patients, but may also result in the identification of targets for novel therapeutic approaches aimed at treating skin erosions. (c) 2009 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 09/2009; 149A(9):1942-7. DOI:10.1002/ajmg.a.32794 · 2.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mutations in the transcription factor gene p63 are causative for human developmental syndromes characterized by three main hallmarks: ectodermal dysplasia, limb malformations and orofacial clefting. Five different dominantly inherited human syndromes and two non-syndromic conditions have been linked to p63 gene defects. Ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome (EEC) is the most common p63-associated condition, since approximately 60 percent of all p63 mutations have been identified in EEC syndrome patients. Other p63-linked syndromes: AEC, LMS, ADULT and RHS, all show overlapping features of the three main disease characteristics. In contrast, isolated split hand/foot malformation (SHFM4) and non-syndromic cleft lip/palate (NSCL) only show one of the three main hallmarks. In this study I have tried to get more insight into the p63-associated diseases, their molecular disease mechanism and the role of p63 and its downstream signaling in these diseases.
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