Rapp-Hodgkin and Hay-Wells ectodermal dysplasia syndromes represent a variable spectrum of the same genetic disorder

Clements, Suzanne; Techanukul, Tanasit; Holden, Simon; Mellerio, Jemima E.; Dorkins, Huw; Escande, Fabienne; McGrath, John A.

doi:10.1111/j.1365-2133.2010.09859.x

Cited by 38 publications

(31 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lastly, the use of genetically heterogeneous sources of keratinocytes in this type of study is of concern. In fact, genetic background effects are well-known to influence the severity of disease phenotypes as demonstrated by the clinical variability observed in related patients carrying the same TP63 mutation (Bertola et al, 2004; Clements et al, 2010; Dianzani et al, 2003). Further, discarded patient skin is often derived from different body sites.…”

Section: New Approaches Of Modeling Complex Diseases In Vitromentioning

confidence: 99%

Integrating Animal Models and In Vitro Tissue Models to Elucidate the Role of Desmosomal Proteins in Diseases

Koster

Dinella

Chen

et al. 2014

Cell Communication & Adhesion

View full text Add to dashboard Cite

Desmosomes are intercellular junctions that provide tissues with structural stability. These junctions might also act as signaling centers that transmit environmental clues to the cell, thereby affecting cell differentiation, migration, and proliferation. The importance of desmosomes is underscored by devastating skin and heart diseases caused by mutations in desmosomal genes. Recent observations suggest that abnormal desmosomal protein expression might indirectly contribute to skin disorders previously not linked to these proteins. For example, it has been postulated that reduced desmosomal protein expression occurs in patients affected by Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC), a skin fragility disorder caused by mutations in the transcription factor TP63. Currently, it is not clear how these changes in desmosomal gene expression contribute to AEC. We will discuss new approaches that combine in vitro and in vivo models to elucidate the role of desmosomal gene deregulation in human skin diseases such as AEC.

show abstract

Section: New Approaches Of Modeling Complex Diseases In Vitromentioning

confidence: 99%

Integrating Animal Models and In Vitro Tissue Models to Elucidate the Role of Desmosomal Proteins in Diseases

Koster

Dinella

Chen

et al. 2014

Cell Communication & Adhesion

View full text Add to dashboard Cite

show abstract

“…Another p63-associated disorder is the ankyloblepharon-ectodermal defects-cleft lip/ palate (AEC) syndrome, which differs from the EEC syndrome mainly by the severity of the skin phenotype, the occurrence of an eyelid fusion at birth, and the absence of limb malformations. Mutations associated with the AEC syndrome are localized in the C-terminal SAM domain, which is absent in the p53 protein (7,9).…”

mentioning

confidence: 99%

APR-246/PRIMA-1 ^MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

Shen

Bogaard

Kouwenhoven

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

p53 and p63 share extensive sequence and structure homology. p53 is frequently mutated in cancer, whereas mutations in p63 cause developmental disorders manifested in ectodermal dysplasia, limb defects, and orofacial clefting. We have established primary adult skin keratinocytes from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients with p63 mutations as an in vitro human model to study the disease mechanism in the skin of EEC patients. We show that these patient keratinocytes cultured either in submerged 2D cultures or in 3D skin equivalents have impaired epidermal differentiation and stratification. Treatment of these patient keratinocytes with the mutant p53-targeting compound APR-246/PRIMA-1 MET (p53 reactivation and induction of massive apoptosis) that has been successfully tested in a phase I/ II clinical trial in cancer patients partially but consistently rescued morphological features and gene expression during epidermal stratification in both 2D and 3D models. This rescue coincides with restoration of p63 target-gene expression. Our data show that EEC patient keratinocytes with p63 mutations can be used for characterization of the abnormal molecular circuitry in patient skin and may open possibilities for the design of novel pharmacological treatment strategies for patients with mutant p63-associated developmental abnormalities.

show abstract

“…There has been ample evidence that the EEC syndrome is mostly caused by mutations in exons 4-8 of TP63 (altering the DNA-binding domain, amino acids 165-357), whereas the RHS and AEC syndrome are typically generated by mutations in exons 12-14 (altering the SAM domain, amino acids 543-610) (Rinne et al, 2006(Rinne et al, , 2007Clements et al, 2010). Hence, mutations causing RHS should be expected in the SAM domain.…”

Section: Discussionmentioning

confidence: 96%

“…Mutations in the DNA-binding domain typically cause EEC syndrome and SAM domain mutations usually generate either RHS or AEC syndrome (Brunner et al, 2002;Rinne et al, 2007;Clements et al, 2010). Mutations in the tetramerization domain do not show a clustering of specific phenotypes.…”

Section: Introductionmentioning

confidence: 96%

A recurrent TP63 mutation causing EEC3 and Rapp–Hodgkin syndromes

Brueggemann

Bartsch

2016

Clinical Dysmorphology

View full text Add to dashboard Cite

The ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3; OMIM #604292), the Rapp-Hodgkin syndrome (RHS), and various other syndromes are caused by mutations in the TP63 gene, which encodes a p53-like transcription factor. Here, we report on a woman aged 37 years and her daughter aged 3 years with the previously reported c.1028G>A (p.Arg343Gln) mutation in exon 8 of TP63. The mother lacked ectrodactyly, indicating a diagnosis of RHS, whereas the girl presented with all three major features (ectrodactyly, ectodermal dysplasia, clefting) and different minor features (including small and brittle nails, and recurrent conjunctivitis believed to be because of stenotic and blocked nasolacrimal ducts) of the EEC3 syndrome. The EEC and EEC-like syndromes are usually distinguished on the basis of the clinical findings; however, these syndromes show a huge variability in features because of variable expressivity and incomplete penetrance, making the correct clinical assignment difficult. In EEC3 syndrome and RHS, a clustering of mutations in the different domains of TP63 can be observed. Our findings indicate the clinical variability with TP63 mutations and underline that in the case of two syndromes being clinically possible in a patient, the final diagnosis should be assigned only after molecular diagnostics.

show abstract

Rapp-Hodgkin and Hay-Wells ectodermal dysplasia syndromes represent a variable spectrum of the same genetic disorder

Cited by 38 publications

References 26 publications

Integrating Animal Models and In Vitro Tissue Models to Elucidate the Role of Desmosomal Proteins in Diseases

Integrating Animal Models and In Vitro Tissue Models to Elucidate the Role of Desmosomal Proteins in Diseases

APR-246/PRIMA-1 ^MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

A recurrent TP63 mutation causing EEC3 and Rapp–Hodgkin syndromes

Contact Info

Product

Resources

About

Rapp-Hodgkin and Hay-Wells ectodermal dysplasia syndromes represent a variable spectrum of the same genetic disorder

Cited by 38 publications

References 26 publications

Integrating Animal Models and In Vitro Tissue Models to Elucidate the Role of Desmosomal Proteins in Diseases

Integrating Animal Models and In Vitro Tissue Models to Elucidate the Role of Desmosomal Proteins in Diseases

APR-246/PRIMA-1 MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

A recurrent TP63 mutation causing EEC3 and Rapp–Hodgkin syndromes

Contact Info

Product

Resources

About

APR-246/PRIMA-1 ^MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations