Spectrum of p63 mutations in a selected patient cohort affected with ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC)

Department of Human Genetics, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 09/2009; 149A(9):1948-51. DOI: 10.1002/ajmg.a.32793
Source: PubMed


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.

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Available from: Tuula Rinne, Oct 17, 2014
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    • "Notably, Cα uniquely harbors the sterile α-motif (SAM) domain ( p63 SAM ), which is a protein-protein interaction domain (Qiao and Bowie, 2005; Thanos and Bowie, 1999), and the transcription inhibitory (TI) domain ( p63 TI ) (Serber et al., 2002). The significance of Cα is evident from genetic studies of p63-associated EDs, showing that mutations in either the p63 SAM or p63 TI domain or a complete absence of Cα/β but not Cγ cause ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome and limb-mammary syndrome (LMS) (Barrow et al., 2002; Celli et al., 1999; Rinne et al., 2009; van Bokhoven et al., 2001). A recent study has shown that a point "
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    ABSTRACT: The transcription factor p63 (Trp63) plays a key role in homeostasis and regeneration of the skin. The p63 gene is transcribed from dual promoters, generating TAp63 isoforms with growth suppressive functions and dominant-negative ΔNp63 isoforms with opposing properties. p63 also encodes multiple carboxy (C)-terminal variants. Although mutations of C-terminal variants have been linked to the pathogenesis of p63-associated ectodermal disorders, the physiological role of the p63 C-terminus is poorly understood. We report here that deletion of the p63 C-terminus in mice leads to ectodermal malformation and hypoplasia, accompanied by a reduced proliferative capacity of epidermal progenitor cells. Notably, unlike the p63-null condition, we find that p63 C-terminus deficiency promotes expression of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1) (Cdkn1a), a factor associated with reduced proliferative capacity of both hematopoietic and neuronal stem cells. These data suggest that the p63 C-terminus plays a key role in the cell cycle progression required to maintain the proliferative potential of stem cells of many different lineages. Mechanistically, we show that loss of Cα, the predominant C-terminal p63 variant in epithelia, promotes the transcriptional activity of TAp63 and also impairs the dominant-negative activity of ΔNp63, thereby controlling p21(Waf1/Cip1) expression. We propose that the p63 C-terminus links cell cycle control and the proliferative potential of epidermal progenitor cells via mechanisms that equilibrate TAp63 and ΔNp63 isoform function. © 2015. Published by The Company of Biologists Ltd.
    Development 12/2014; 142(2). DOI:10.1242/dev.118307 · 6.46 Impact Factor
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    • "The TI domain interacts with the TA domain and masks residues relevant for TA, thus suppressing TAp63-mediated TA [Yang et al., 1998; Serber et al., 2002]. Some genotype–phenotype correlations, such as EEC syndrome associating with mutations in the DBD, and RHS and AEC syndromes with mutations preferentially clustering in the SAM and TI domains [Rinne et al., 2009; Clements et al., 2010], suggest a complex and heterogenous pathogenesis for the TP63-related disorders. We report on a 3-month-old boy and his affected mother displaying a highly variable phenotype and sharing a previously unreported TP63 mutation. "
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    ABSTRACT: Heterozygous mutations in TP63 cause a wide spectrum of autosomal dominant developmental disorders variably affecting skin, limbs, and face. TP63 encodes p63, a protein expressed in two main isoforms (Tap63 and ΔNp63) with critical roles in both cell differentiation and development. Some analyses suggest a relationship of the mutation site to the observed clinical picture, although this link is inconsistent. This suggests an appreciable phenotypic continuity within the TP63-related disorders. We report a 3-month-old boy ascertained for congenital scalp erosion and mild features of ectodermal dysplasia. His mother showed full-blown characteristics of Rapp-Hodgkin syndrome plus intense abdominal and popliteal freckling. Molecular investigation identified the novel TP63 mutation c.1697delG. We used a luciferase reporter assay to compare the effects on the p63 transactivation (TA) activity of c.1697delG with that of the p.Arg280Cys and p.Gln634X mutations, associated with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome and isolated split hand/foot malformation, respectively. These results demonstrated complex behavior of c.1697delG in the TA of genes involved in epidermal differentiation and development and shed further light in the physiopathology of TP63-related disorders.
    American Journal of Medical Genetics Part A 12/2011; 155A(12):3104-9. DOI:10.1002/ajmg.a.34335 · 2.16 Impact Factor
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    • "Skin biopsies, hair and blood samples were donated by many affected participants through a Baylor College of Medicine IRB-approved protocol. These specimens were evaluated for histopathologic changes [see Dishop et al, 2009 this issue] and the DNA sequenced to determine the location of mutations [see Rinne et al, 2009 this issue]. The tissues were also evaluated for p63 and other associated genes through immunohistochemistry and in-situ hybridization [see Koster et al and Beaudry et al, 2009 this issue]. "
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    ABSTRACT: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (Hay-Wells syndrome, MIM #106220) is a rare autosomal dominant ectodermal dysplasia syndrome. It is due to mutations in the TP63 gene, known to be a regulatory gene with many downstream gene targets. TP63 is important in the differentiation and proliferation of the epidermis, as well as many other processes including limb and facial development. It is also known that mutations in TP63 lead to skin erosions. These erosions, especially on the scalp, are defining features of AEC syndrome and cause significant morbidity and mortality in these patients. It was this fact that led to the 2003 AEC Skin Erosion Workshop. That conference laid the groundwork for the International Research Symposium for AEC Syndrome held at Texas Children's Hospital in 2006. The conference brought together the largest cohort of individuals with AEC syndrome, along with a multitude of physicians and scientists. The overarching goals were to define the clinical and pathologic findings for improved diagnostic criteria, to obtain tissue samples for further study and to define future research directions. The symposium was successful in accomplishing these aims as detailed in this conference report. Following our report, we also present 11 manuscripts within this special section that outline the collective clinical, pathologic, and mutational data from 18 individuals enrolled in the concurrent Baylor College of Medicine IRB-approved protocol: Characterization of AEC syndrome. These collaborative findings will hopefully provide a stepping-stone to future translational projects of TP63 and TP63-related syndromes.
    American Journal of Medical Genetics Part A 09/2009; 149A(9):1885-93. DOI:10.1002/ajmg.a.32761 · 2.16 Impact Factor
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