| SUMMARY OF RESEARCH BEING UNDERTAKEN
Background
Epidermolysis Bullosa – EB is a set of genetically inherited skin blistering
conditions affecting an estimated 1 in 17,000 of the world’s population. Junctional
EB is the severest, and is most frequently fatal in infancy. Research has found that it is
caused by a fault in the genes at the junction between the dermis and the epidermis. This
research seeks to further knowledge and understanding of the causes and contribute to
devising gene therapy experiments.
Laymans Summary
The group has discovered an abundant cytoskeletal protein (p27BBP) that
associates with the junctional domain of the integrin subunit b 4. Since mutations of the
junctional domain b 4 lead to severe forms of EB with pyloric atresia, it is highly
probable that p27BBP may also be involved in the onset of EB. For this reason
Dr Biffo wants to analyse cases of EB of unknown origin and to see whether mutations of
the p27BBP can be found. There will be collaboration with Prof Meneguzzi at
INSERM in Nice.
Scientific Abstract
The integrin subunit b 4 is necessary for hemidesmosome formation, and mutations in its
cytoplasmic domain cause junctional EB with pyloric atresia. b 4 mediates its function
through the association of unknown cytoskelatal proteins to its cytoplasmic tail. In spite
of this, their identification has been hampered by their biochemical insolubility. By
using the yeast two hybrid system, they have recently isolated a cytoplasmic interactor of
the integrin subunit b 4 named p27 BBP. Several data indicate that p27BBP is
likely to be the long term sought link between b 4 and the cytoskeleton:
it associates specifically with the functional domain of b 4, and is expressed in all
cells that express b 4;
it is a novel protein with several features of a structural component of the cell;
it is associated with the intermediate filament cytoskeleton.
The purpose of this research is to assess whether anomalies in p27BBP expression
or p27BBP mutations can result in EB. In collaboration with the group of Dr
Meneguzzi in Nice, samples of patients affected by Junctional EB, will be analysed for the
presence of p27BBP mutations. The techniques employed will be
immunohistochemistry on skin specimens using an antibody raised against p27BBP, and
genetic analysis of the probands’ genomic DNA. This study may lead to the
identification of the mutated gene in kindreds that have no genetic defects in the genes
(LAMA3, LAMB3, LAMC2, BPAG2, ITGA6, ITGB4, or PLEC1) thus far involved in EB conditions
caused by altered hemidesmosomes.
Conclusion
In the short term this is a project which diagnosis and classifies EB. In the longer
term if as a result of this research this protein turns out to be fundamental in
epithelial cell survival, then this will assist in exploring treatments relying on gene
therapy. This study aims to identify the cause of EB in the cases in which no mutated
genes have so far been discovered. The fact that p27BBP is downstream of LAM, b
4, L6 (genes that are mutated in Junctional EB) may also help to devise gene therapy
experiments aimed at restoring normal skin. |
