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Structural and Functional Analysis of the Dominant Plectin Mutation in EBS-Ogna (Wiche 2)

Project lead Prof G Wiche
Organisation Max Perutz Labs Vienna, Vienna, AUSTRIA
Project budget GBP 95,036.00
Start date / Duration 01. Jan 2008 / 24 months
Funder(s) / Co-Funder(s) DEBRA UK, EB MSAP/EBEP Recommended
Research area Molecular therapy

Project details

Scientific summary

Plectin is a protein that links several systems within the cell and anchors them to the cell membrane.  Because of these properties, plectin is important for maintaining the integrity of cells and protecting them against mechanical stress, particularly in skin and muscle.  People who lack plectin, because they have mutations in the plectin gene, develop EB simplex (EBS) and muscular dystrophy (MD).

Most plectin mutations are inherited in an autosomal recessive mode, i.e. the symptoms only appear when a copy of the defective gene is inherited from both parents; technically when two alleles of the plectin gene carry nonsense mutations.  Normally, where only one copy of the defective gene is inherited there is no abnormality.

However, a unique plectin mutation has been described that is only present in one allele but the individuals carrying it are affected by disease, known as a dominant mutation.  This mutation leads to the skin disease EBS-Ogna.

Besides being the only dominant mutation in the plectin gene known so far, other hallmarks of EBS-Ogna are that the mutation causes an interesting change in a single amino acid and that it manifests exclusively in skin whilst muscle is spared.  These hallmarks make EBS-Ogna particularly interesting to study since it could provide insights into the function of plectin specifically in the skin. 

Strategic relevance

In this project, the researchers propose to investigate how the Ogna mutation causes skin blistering by taking a dual experimental approach; a genetic approach using modified mice and a biochemical approach using purified recombinant proteins. 

The mice will carry an Ogna-related plectin allele, thus mimicking Ogna patients.  These mice, and the cell lines derived from them, will allow study of the mechanisms of the EBS-Ogna syndrome at the levels of the whole animal, cells and molecules.  The biochemical approach will be aimed at identifying lost or new binding partners of Ogna-plectin in comparison to wild-type plectin.

Furthermore, the Ogna mouse could be used as an animal model for testing pharmaceutical drugs to alleviate the symptoms of the condition and for developing gene therapy.

What did this project achieve?

The research team believed the prime goals of this research project have been achieved. Ogna knock-in mice mimic the skin pathology of human carriers of the mutation. The heterozygous as well as the homozygous knock-in mouse lines generated were viable and fertile, and thus can serve as an animal model for EBS-Ogna and potentially other forms of EB. Ogna mice seem well suited for proof of principle studies in gene and cell therapies. Plectin 1a levels in skin provide a readout for HD status, suitable to follow the evolution of the condition after correction on genetic or cellular levels, or by pharmacological means. Some of these approaches are being explored by other groups that have already received the group's mice. Although there was no time to dissect the molecular mechanism which will explain the dominance of the mutation in full depth, the research team has opened a new line of research that they would like to complete in the future. Specifically, they would like to characterize the proteolytic activities that lead to the degradation of plectin 1a in keratinocytes and find ways to suppress them. Studies along these lines would also provide an excellent opportunity for the training of a junior postdoc in the near future.


Wiche 2
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