scholarly journals Isoform-Specific Roles of Mutant p63 in Human Diseases

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 536
Author(s):  
Christian Osterburg ◽  
Susanne Osterburg ◽  
Huiqing Zhou ◽  
Caterina Missero ◽  
Volker Dötsch
Keyword(s):  
Cleft Lip ◽  
Ectodermal Dysplasia ◽  
Skin Development ◽  
Disease Mechanisms ◽  
Skin Fragility ◽  
Cleft Lip Palate ◽  
Life Threatening ◽  
Functional Consequences ◽  
Development And Differentiation

The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the DNA binding domain cause Ectrodactyly, Ectodermal Dysplasia, characterized by limb deformation, cleft lip/palate, and ectodermal dysplasia while mutations in in the C-terminal domain of the α-isoform cause Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility, severe, long-lasting skin erosions, and cleft lip/palate. The molecular disease mechanisms of these syndromes have recently become elucidated and have enhanced our understanding of the role of p63 in epidermal development. Here we review the molecular cause and functional consequences of these p63-mutations for skin development and discuss the consequences of p63 mutations for female fertility.

scholarly journals Protein aggregation of the p63 transcription factor underlies severe skin fragility in AEC syndrome

2018 ◽  
Vol 115 (5) ◽  
pp. E906-E915 ◽  
Author(s):  
Claudia Russo ◽  
Christian Osterburg ◽  
Anna Sirico ◽  
Dario Antonini ◽  
Raffaele Ambrosio ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Cleft Lip ◽  
Underlying Disease ◽  
Dominant Negative ◽  
Negative Effects ◽  
Mutant Proteins ◽  
Skin Fragility ◽  
Cleft Lip Palate ◽  
Life Threatening ◽  
Development And Differentiation

The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the C-terminal domain of the p63 gene can cause ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility and severe, long-lasting skin erosions. Despite deep knowledge of p63 functions, little is known about mechanisms underlying disease pathology and possible treatments. Here, we show that multiple AEC-associated p63 mutations, but not those causative of other diseases, lead to thermodynamic protein destabilization, misfolding, and aggregation, similar to the known p53 gain-of-function mutants found in cancer. AEC mutant proteins exhibit impaired DNA binding and transcriptional activity, leading to dominant negative effects due to coaggregation with wild-type p63 and p73. Importantly, p63 aggregation occurs also in a conditional knock-in mouse model for the disorder, in which the misfolded p63 mutant protein leads to severe epidermal defects. Variants of p63 that abolish aggregation of the mutant proteins are able to rescue p63’s transcriptional function in reporter assays as well as in a human fibroblast-to-keratinocyte conversion assay. Our studies reveal that AEC syndrome is a protein aggregation disorder and opens avenues for therapeutic intervention.

The role of audiological diagnostics in children with cleft lip & palate (CLP)

2009 ◽  
Vol 73 (10) ◽  
pp. 1365-1367 ◽  
Author(s):  
Silky Luthra ◽  
Satbir Singh ◽  
Anu N. Nagarkar ◽  
J.K. Mahajan
Keyword(s):  
Cleft Lip ◽  
Cleft Lip Palate

scholarly journals A novel c.1037C > G (p.Ala346Gly) mutation in TP63 as cause of the ectrodactyly-ectodermal dysplasia and cleft lip/palate (EEC) syndrome

2015 ◽  
Vol 38 (1) ◽  
pp. 37-41 ◽  
Author(s):  
Leandro Ucela Alves ◽  
Eliete Pardono ◽  
Paulo A. Otto ◽  
Regina Célia Mingroni Netto
Keyword(s):  
Cleft Lip ◽  
Ectodermal Dysplasia ◽  
Eec Syndrome ◽  
Cleft Lip Palate

scholarly journals Single-cell RNA-seq identifies a reversible epithelial-mesenchymal transition in abnormally specified epithelia of p63 EEC syndrome

2018 ◽  
Author(s):  
Eduardo Soares ◽  
Quan Xu ◽  
Qingqing Li ◽  
Jieqiong Qu ◽  
Yuxuan Zheng ◽  
...  
Keyword(s):  
Cell Fate ◽  
Developmental Disorders ◽  
Cleft Lip ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Disease Mechanisms ◽  
Eec Syndrome ◽  
Cleft Lip Palate ◽  
Induced Pluripotent ◽  
Stratified Epithelia

AbstractMutations in transcription factor p63 are associated with developmental disorders that manifest defects in stratified epithelia including the epidermis. The underlying cellular and molecular mechanism is however not yet understood. We established an epidermal commitment model using human induced pluripotent stem cells (iPSCs) and characterized differentiation defects of iPSCs derived from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients carrying p63 mutations. Transcriptome analyses revealed distinct step-wise cell fate transitions during epidermal commitment; from multipotent simple epithelium to basal stratified epithelia, and ultimately to the mature epidermal fate. Differentiation defects of EEC iPSCs caused by mutant p63 occurred during the specification switch from the simple epithelium to the basal stratified epithelial fate. Single-cell transcriptome and pseudotime analyses identified signatures of embryonic epithelial-mesenchymal transition (EMT) associated with the deviated commitment route of EEC iPSCs. Repressing mesodermal activation reversed the EMT and enhanced epidermal commitment. Our findings demonstrate that p63 is required for specification of stratified epithelia, probably by repressing embryonic EMT during epidermal commitment. This study provides insights into disease mechanisms underlying stratified epithelial defects caused by p63 mutations and suggests potential therapeutic strategies for the disease.Significance statementMutations in p63 cause several developmental disorders with defects of epithelial related organs and tissues including the epidermis. Our study is to dissect the unknown cellular and molecular pathomechanism. We utilized human induced pluripotent stem cells (iPSCs) derived from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients carrying p63 mutations and studied transcriptome changes during differentiation of these cells to epidermal cells. Our analyses showed that the specification of the proper epithelial cell fate was affected by p63 EEC mutations, with an abnormal embryonic epithelial-mesenchymal transition (EMT). Repressing mesodermal activation reversed the EMT and enhanced epidermal commitment. This study provides insights into disease mechanisms associated with p63 mutations and suggests potential therapeutic strategies.

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