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.

Download full-text


Available from: Tuula Rinne, Oct 17, 2014
  • Source
    • "Missense and frameshift mutations in exons 13 and 14, which encode the sterile alpha motif (SAM) and the transactivation inhibitory (TI) domains, account for the vast majority of mutations in AEC. However, while the RHS/AEC syndromes have been consistently linked to the α-tail of the TP63 gene, nonsense mutations in the 5 end of the gene have also been recently described [13] [14]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the TP63 gene have been associated with a variety of ectodermal dysplasia syndromes, among which the clinically overlapping Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) and the Rapp-Hodgkin syndromes. We report a multiplex nonconsanguineous family of Ashkenazi-Jewish descent, in which the index patient presented with a persistent scalp skin lesion, dystrophic nails and light thin hair. Further evaluation revealed over 10 affected individuals in the kindred, over four generations, exhibiting varying degrees of ectodermal involvement. Analysis of the TP63 gene from four of the patients and from two healthy individuals of the same family was performed. Gene sequencing of the patients revealed a nonsense mutation leading to a premature termination codon (PTC) (p.Gln16X). The same mutation was found in all tested affected individuals in the family, but gave rise to marked phenotypic variability with minor clinical manifestations in some individuals, underscoring the clinical heterogeneity associated with the recently described PTC-causing mutations.
    Fetal and pediatric pathology 10/2015; DOI:10.3109/15513815.2015.1095261 · 0.48 Impact Factor
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
Show more