SUMMARY OF RESEARCH BEING UNDERTAKEN

Plectin is a protein that can link different cell skeletal systems to one another but also connects the intermediate filament system to the plasma membrane by binding to the ß4 subunit of the integrin ?6ß4 in hemidesmosomes. In this capacity, it plays an important role in maintaining the architecture of the cell and the integrity of the skin. Many epidermolysis bullosa simplex (EBS) patients that develop late onset muscular dystrophy carry nonsense mutations in the exon 31 part of the plectin gene. These patients lack the full-length plectin molecule but most of them may still express a reduced, rod-less variant of plectin.

Whether this rod-less variant is functional is not known. However, because patients who express this rod-less variant have a relatively favourable course of the condition, as compared to patients who are expected not to express any plectin protein at all, it may fulfil some of the important functions of the intact plectin molecule. Moreover, it has been shown that mice lacking plectin die within 2-3 days after birth and display symptoms similar to that of a patient who suffers from a lethal form of EBS due to nonsense mutations outside of the part of the gene that makes the rod domain of plectin. It is predicted that the rod-less plectin variant, in contrast to full-length plectin, has lost its ability to crosslink    ?6ß4 molecules to one another within the cell. We believe that this cross-linking property of plectin is critical for the formation of functioning hemidesmosomes.

In this project the function of the rod-less plectin molecule will be studied and the hypothesis tested that its presence in EBS-MD patients is responsible for a favourable course of the condition. It is proposed to generate mice, whose plectin gene no longer contains exon-31, and therefore are genetically equivalent to EBS-MD patients. These mice will allow us to test the hypothesis that the rod-less plectin variant has an important compensatory function in EBS-MD patients in whom full-length plectin protein is absent.

Furthermore, these mice will be useful to unravel the function of the plectin variant in the assembly and integrity of hemidesmosomes and to confirm why there is a difference in functionality between the rod-less variant and the intact molecule.

FINANCIAL SUMMARY