Biology of anchoring fibrils: lessons from dystrophic epidermolysis bullosa.
Anchoring fibrils are adhesive suprastructures that ensure the connection of the epidermal basement membrane with the dermal extracellular matrix. The fibrils represent polymers of collagen VII, the major structural fibril component, but may also contain other proteins. Remarkable progress has been made in the last few years in understanding the functions of skin basement membrane components including the anchoring fibrils. Novel insights into the biology of the anchoring fibrils have been gained from experimental studies on dystrophic epidermolysis bullosa (DEB), a group of inherited blistering disorders caused by mutations in the gene for collagen VII, COL7A1. Mutation analyses of DEB families have disclosed more than 100 COL7A1 gene defects so far, but the unusual complexity of the mutation constellations and their biological consequences are only beginning to emerge. In analogy to heritable disorders of other collagen genes, predictable phenotypes of COL7A1 mutations causing premature termination codons or dominant negative interference have been observed. However, collagen VII seems to represent a remarkable exception among collagens in that many mutations, including heterozygous glycine substitutions and deletions, lead to minimal phenotypes, or to no phenotype at all. In contrast to fibrillar collagens, structural abnormalities of collagen VII molecules in anchoring fibrils appear to be tolerated to a certain extent. However, the mild DEB phenotypes can be severely modulated by a second aberration in individuals compound heterozygous for two different COL7A1 mutations. Therefore, not only definition of mutation(s) but also cell biological, protein chemical and suprastructural studies of the mutated molecules yield novel insight into the molecular pathomechanisms underlying disease.
Bruckner-Tuderman
L
L
Department of Dermatology, University of Münster, Germany. tuderma@uni-muenster.de
Höpfner
B
B
Hammami-Hauasli
N
N
D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D020405:Dermis / Q000033:anatomy & histology / Q000473:pathology / Q000502:physiology*; D004817:Epidermis / Q000033:anatomy & histology / Q000473:pathology / Q000502:physiology*; D016108:Epidermolysis Bullosa Dystrophica / Q000235:genetics* / Q000473:pathology; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D008024:Ligands; D010641:Phenotype
D001323:Autoantibodies; D008024:Ligands; D003094:Collagen