TY  - JOUR
A1  - Russo, Claudia
A1  - Osterburg, Christian
A1  - Sirico, Anna
A1  - Antonini, Dario
A1  - Ambrosio, Raffaele
A1  - Würz, Julia
A1  - Rinnenthal, Jörg
A1  - Ferniani, Marco
A1  - Kehrlößer, Sebastian
A1  - Schäfer, Birgit
A1  - Güntert, Peter
A1  - Sinha, Satrajit
A1  - Dötsch, Volker
A1  - Missero, Caterina
T1  - Protein aggregation of the p63 transcription factor underlies severe skin fragility in AEC syndrome
T2  - Proceedings of the National Academy of Sciences of the United States of America
N2  - 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.
KW  - AEC syndrome
KW  - mouse model
KW  - p63
KW  - protein aggregation
KW  - skin
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/45656
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-456569
SN  - 1091-6490
SN  - 0027-8424
N1  - This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).
VL  - 115
IS  - 5
SP  - E906
EP  - E915
PB  - National Acad. of Sciences
CY  - Washington, DC
ER  -