Fifth International Conference on the Molecular Biology and Pathology of Matrix 395
contribution of the collagen type V abnormalities to the phenotype of this patient is unclear. In view of the observed anchoring fibrils alterations, mutation analy- sis of the COL7A1 gene is still ongoing (Dr. L. Bruckner-Tuderman, Miinster).
We wonder whether compound heterozygosity for two different (helical) amino acid substitutions in this child might have a deleterious effect on collagen type V function and its interaction with other EC proteins and as such have any phenotypic consequence in this patient.
the formation of anchoring fibrils. As additional mutations in COLTA1 in DEB are characterized, we can begin to classify, diagnose and eventually treat patients on the basis of their molecular defects.
Linkage of Pretibial Dystrophic E p i d e r m o l y s i s Bullosa to C O L 7 A I : Expansion of the Phenotypic Spectrum of Collagen T y p e VII Defec t s
7. Defects in Type VII Collagen
Heterogeneity of Mutations in the T y p e VII Collagen Gene ( C O L 7 A 1 ) in D i f f e r e n t Forms of Dystrophic Epidermolysis Bul lo sa
Angela M. Christiano*, Alain Hovnanian~, Daniel S. Greenspanqt and Jouni Uitto*
"Jefferson Medical College, Philadelphia, PA, USA; tlNSERM, Paris, France; and ~University of Wisconsin, Madison, WI, USA
The spectrum of clinical severity and inheritance patterns in the different forms of dystrophic epider- molysis bullosa appear to reflect different types and combinations of mutations within the type VII colla- gen gene. We recently reported a homozygous mis- sense mutation (M2798K) in two siblings with the mild (mitis) form of RDEB. This mutation is thought to interfere with anchoring fibril assembly, resulting in a mild phenotype in affected individuals, while hetero- zygous carriers were clinically normal. In contrast, in three Hallopeau-Siemens RDEB patients with prema- ture termination codons in the homozygous state, the consequences are profound: two premature termina- tion codons lead to the absence of any full-length type VII collagen, and as a result, no detectable anchoring fibrils. We have observed heterozygous PTCs in fourteen additional HS-RDEB patients, and we predict their second mutation will also be a PTC. Interest- ingly, we have recently observed PTCs on one allele of two patients with the mitis form of RDEB, suggesting that in these patients, the second mutation must con- tribute to the striking difference in phenotype. We predict that the second mutation in these patients will be a subtle mutation, such as M2798K, which inter- feres with assembly. Furthermore, in a two different DDEB families, we recently identified distinct glycine substitutions in the twelfth triple-helical region of COL7A1, which exert a dominant/negative effect on
A. De Paepe, L. Nuytinck, S. De Bie and J.M. Naeyaert
Department of Medical Genetics and Dermatology, University Hospital Gent, Belgium
Dystrophic Epidermolysis Bullosa (DEB) comprises various dominant and recessive blistering diseases, ranging from mild to very severe. Anchoring fibrils (AF), responsible for attachment of epidermis to der- mis are abnormal, diminished or absent in DEB. The major protein of AF is collagen type VII, encoded by the COL7A1 gene on chromosome 3q21.1.
We have identified a large family with a special form of dominant DEB, characterized by lichenoid lesions in the pretibial area, but also on the trunk. Ultrastructural examination showed no major struc- tural abnormalities of AF. Immunostaining with an antibody LH7:2 against the NC1 domain of collagen VII was positive at the roof and the bottom of the subepidermal blisters. Linkage analysis with two intragenic COL7A1 markers was performed on 29 individuals in three generations. A lodscore of 4.71 at e = 0 was obtained, suggesting linkage with COL7A1. Heterozygosity for a COL7A1 mutation most proba- bly causes EB in this family. Further mutation analy- sis will clarify the biological effect of the mutation on AF structure and assembly.