Cornerstone for therapy elucidated cause of serious hereditary disease

Serious hereditary disease: discovered cause of AEC syndrome

Researchers from Germany and Italy have discovered the cause of a serious hereditary disease. The life-threatening ankyloblepharon ectodermal dysplasia-clefting syndrome (AEC syndrome) is therefore caused by pathological protein aggregates. The new findings could form the basis for a causal therapy.

Foundation for the development of new therapeutic approaches

Mutations in the p63 protein lead to a number of disease syndromes, but none is as serious as the AEC syndrome, according to a statement by the Goethe University Frankfurt am Main. Researchers at the University of Naples have discovered this Syndrome Diseases such as Alzheimer's, Parkinson's or ALS are more similar than other p63-based syndromes. With their work published in the journal "Proceedings of the National Academy of Sciences" (PNAS), they lay the foundation for the development of new therapeutic approaches.

Researchers have uncovered the cause of a serious hereditary disease. The lethal AEC syndrome is therefore caused by pathological protein aggregates. The new findings could form the basis for a causal therapy. (Image: Sven Hoppe / fotolia.com)

Disorders in embryonic development

Many diseases are based on genetic abnormalities that lead to malfunction of proteins. A well-known and well-studied example is the tumor suppressor p53, whose inactivation is one of the first steps in the development of cancer.

In contrast, mutations of the related protein p63 lead to a group of syndromes characterized by disturbances in embryonic development.

p63 acts as a transcription factor in the epidermal stem cells and regulates their development and proliferation.

Mutations in a specific area of ​​the protein cause life-threatening ankyloblepharon ectodermal dysplasia-clefting syndrome (AEC syndrome).

Children are born with cleft lip and palate

The AEC syndrome, also known as Hay Wells syndrome, "is an autosomal dominant disease", according to the portal of the self-help group Ectodermal Dysplasia e.V.

The disease is characterized, among other things, by the fact that children are born with cleft lip and palate and sustained losses of the epidermis (erosions), comparable to severe burns.

"The head hair of those affected is thin and wiry. Eyelashes are sparse or completely absent. The nails may be missing or malformed, "writes the self-help group.

And: "Some sufferers suffer from chronic scalp dermatitis, which is very difficult to treat and can lead to scarring and hair loss."

Individual symptoms of the disease can be surgically repaired or alleviated. An approach to the treatment of the origin, however, was previously impossible because of the lack of understanding of the mutated p63 molecules.

New way to a promising treatment

The mutations causing the AEC syndrome are confined to two domains of p63 and do not overlap those of the other p63-associated syndromes.

These domains are considered to be platforms for protein-protein interactions, and so it has been assumed that the disease is triggered by a loss of binding partners.

"Instead, it has been shown that the mutations lead to the exposure of hydrophobic amino acid sequences that assemble in the cell and form large, unstructured complexes," explains Prof. Volker Dötsch from the Institute of Biophysical Chemistry at the Goethe University.

In this way, the mutant p63 loses its functions as a stem cell factor. Similar types of protein aggregates are also the cause of other diseases such as Alzheimer's, Parkinson's or ALS.

In order to elucidate the novel mechanism in detail, many different biochemical, biophysical and cell biological methods as well as a mouse model of the syndrome were necessary.

A success that was only possible through the close and interdisciplinary collaboration with the group of Prof. Caterina Missero of the University of Naples.

In addition, the scientists were able to show that p63 regains its function by dissolving the aggregates. This opens up a new path to promising treatment of the causes of AEC syndrome. (Ad)