The cornerstone of therapy: the cause of serious hereditary disease has been elucidated

Serious inherited disorder: cause of AEC syndrome discovered

Researchers from Germany and Italy have uncovered 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 causal therapy.

Foundation stone 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 AEC syndrome, according to a statement by Goethe University Frankfurt am Main. Researchers at the Frankfurt University of the University of Naples have now discovered that this Syndrome diseases like 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 foundations for the development of new therapeutic approaches.

Disorders in embryonic development

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

Mutations of the related protein p63, on the other hand, lead to a group of syndromes that are characterized by disorders in embryonic development.

p63 acts as a transcription factor in the stem cells of the epidermis and regulates their development and reproduction.

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

Children are born with cleft lip and palate

AEC syndrome, which is also known as Hay-Wells syndrome, "is an autosomal dominant disease," says 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 suffer permanent losses of the epidermis (erosions), comparable to severe burns.

“The hair on the head of those affected is thinning and wiry. Eyelashes are sparse or missing. The nails can be missing or deformed, ”writes the self-help group.

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

Individual symptoms of the disease can be surgically corrected or alleviated. However, an approach to treating the origin was previously impossible due to the lack of understanding about the mutated p63 molecules.

New way to a promising treatment

The mutations that cause AEC syndrome are limited to two domains of p63 and do not overlap with those of the other p63-associated syndromes.

These domains are considered platforms for protein-protein interactions, and it was previously thought that the disease was triggered by the loss of binding partners.

"Instead, we were able to show 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 Goethe University.

In this way the mutated 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 from 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)

Author and source information

Video: The end of genetic disease. Jacob Corn. TEDxBerkeley (January 2022).