HomeENGLISH MAGAZINEThe sick gene "shifts the skin": the case for AEC syndrome

The sick gene “shifts the skin”: the case for AEC syndrome

The origin of many diseases lies in the genetic anomalies that cause malfunctions in the proteins that encode. A well-known and widely studied example is p53, a tumor suppressor protein (tumor suppressor). The inactivation of p53 is one of the first stages in the development of a tumor. Mutations in the p63 homologous protein, however, lead to a group of syndromes characterized by defects in embryonic development. The p63 transcription factor works in stem cells of the upper skin (epidermis) and regulates their development and proliferation. Heterozygous mutations in p63 (TP63) are causative of a group of autosomal dominant human disorders characterized by various combinations of ectodermal dysplasia, orofacial clefting, and limb malformations. Among these disorders, ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome is mainly characterized by severe ectrodactyly and limb defects, whereas in ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC), the distinguishing features are ankyloblepharon, congenital erythroderma, skin fragility, atrophy, palmoplantar hyperkeratosis, and extensive skin erosions. Distinct p63 mutations can also cause nonsyndromic diseases, including isolated split hand/foot malformation (SHFM4) 

Mutations in a certain part of the protein are responsible for the potentially lethal ankyloblefaro disorder – ectodermal dysplasia – clefting (AEC syndrome), which is characterized, for example, by cleft palate and long-lasting skin erosions similar to severe burns. Some symptoms may be remedied or alleviated with surgery, but so far no approach to treating the cause has been possible due to the lack of knowledge about the mutated p63 molecules. Scientists at Goethe University in Frankfurt, in collaboration with a research group at the University of Naples Federico II, have now discovered that this syndrome resembles diseases such as Alzheimer’s, Parkinson’s or ALS compared to other p63-based syndromes. Their results, which were recently published in the scientific journal Proceedings of the National Academy of Sciences (PNAS), lay the groundwork for the development of new therapies. The mutations that cause the cluster of AEC syndrome in two domains of the p63 protein do not overlap with those of the other syndromes associated with it. Because these domains are known to be a platform for protein-protein interactions, it has so far been hypothesized that the disorder is triggered through a loss of such interactions.

The biological significance of this interaction remains to be determined. Since p63 is an abundantly expressed transcription factor in keratinocytes, and AEC mutants often show a longer half-life in cells than the wild-type protein, mutant p63 may be able to sequester other nuclear proteins. Aggregation between AEC mutants and p73 and/or other p63 protein partners helps explain the severe skin phenotype specifically observed in AEC syndrome and not in other diseases associated with p63 mutations. “Instead, we were able to demonstrate that mutations within p63 expose sequences of hydrophobic amino acids that attach to each other in the cell and form large unstructured complexes (aggregates similar to the beta-amyloid in Alzheimer’s). This leads to the loss of the function of p63 as a stem cell factor”, explains Professor Volker Dötsch from the Institute of Biophysical Chemistry at the Goethe University in Frankfurt. Similar types of protein aggregates also cause other diseases, such as Parkinson’s, Alzheimer’s, or ALS. Researchers were also able to demonstrate that p63 resumes its activity once aggregate formation is blocked. 

A great variety of biological, biochemical, biophysical and cellular methods were needed as well as a mouse model of the disorder to decipher this new mechanism in detail. A success that was only possible thanks to the close and interdisciplinary collaboration with the research group led by Professor Caterina Missero at the University of Naples Federico II. 

  • a cura del Dr. Gianfrancesco Cormaci, PhD, specialista in Biochimica Clinica.

Scientific references

Russo C et al., Missero C. PNAS USA. 2018 Jan; 115(5):E906-E915. 

Busa T et al., Touraine R. Am J Med Genet A. 2017;173(11):3114-17.

Richardson R et al. PLoS Genet. 2017 Jun 12; 13(6):e1006828.

Khandelwal KD, Ockeloen CW et al. Am J Med Genet. 2017 May 17. 

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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