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

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.