Genetic linkage to the type VII collagen gene (COL7A1) in 26 families with generalised recessive dystrophic epidermolysis bullosa and anchoring fibril abnormalities.

Abstract

To strengthen the evidence for genetic linkage to COL7A1, we have studied 26 generalised recessive dystrophic epidermolysis bullosa (EB) families of British, Italian, Irish, and South African origin. We chose two linkage markers, a COL7A1 PvuII intragenic polymorphism and a highly informative anonymous microsatellite marker, D3S1100, which maps close to the COL7A1 locus at 3p21.1-3. Diagnosis was established by family history, clinical examination, immunofluorescence, and ultrastructural studies. The PvuII marker was informative in 16 families with a maximum lod score (Zmax) of 3 51 at recombination fraction (0) = 0. The D3S11OO microsatellite was informative in 24 out of 25 families with Zmax=6*8 at 0=0-05 (Z=4-94 at 0=0) and no obligatory recombination events. These data strongly suggest that COL7A1 mutations cause EB in these families and, combined with previous studies, indicate locus homogeneity. The importance ofanchoring fibrils for dermal-epidermal adhesion is further underlined. D3S11OO may later prove useful in prenatal diagnosis of this disease, if used in combination with other markers. (J Med Genet 1994;31:745-748) Epidermolysis bullosa (EB) encompasses a group of inherited diseases characterised by inappropriate blistering of the skin after minor trauma. Clinically it varies from a limited, nonscarring form to a severe mutilating disorder with widespread loss ofskin and scarring. Three major types are separated on the basis of the microscopic level of blistering within the skin': (1) EB simplex with cleavage through the basal epidermis; (2) junctional EB with cleavage through the lamina lucida of the basement membrane; and (3) dystrophic EB with cleavage below the lamina densa of the basement membrane. Dystrophic EB has autosomal dominant and recessive forms. Attempts at further sub-categorisation2 have been based on both clinical and microscopic variation in the phenotype, but there is overlap between categories causing difficulties in precise classification.COL7A1 is the prime candidate gene for both autosomal dominant and recessive dystrophic EB. Anchoring fibrils, visible on electron microscopy as cross banded fanning structures extending from the lower lamina densa into the papillary dermis, are composed mainly of type VII collagen3 and have both qualitative and quantitive abnormalities in dystrophic EB.45 In generalised recessive dystrophic EB, recognisable anchoring fibrils may be missing and immunofluorescence staining with type VII collagen antibodies is markedly reduced or absent.8 Partial cloning of COL7A19 and identification of an intragenic PvuII polymorphism'0 enabled demonstration of tight linkage to dominant dystrophic EB"1'3 and, in one study of 19 patients from France, to generalised recessive dystrophic EB with Zmax = 3 97 at 0 =o.l4 Recently a homozygous insertion-deletion within the N-terminal noncollagenous (NC1) domain of COL7A1 has been recognised in a generalised recessive dystrophic EB patient'5 and a methionine to lysine substitution within the C-terminal non-c...

Type VII Collagen: The Anchoring Fibril Protein at Fault in Dystrophic Epidermolysis Bullosa

“…The subsequent examination of 14 families with DDEB resulted in the combined LOD score of Ẑ = 41.42 at θ= 0, establishing a robust linkage between the type VII collagen gene and the disease locus causing skin fragility in DEB [27]. Similar genetic linkage studies were subsequently performed in families with RDEB, particularly with the most severe, Hallopeau- Siemens type [28, 29]. Again, an unequivocal genetic linkage between COL7A1 and the disease locus in RDEB was established.…”

Epidermolysis bullosa in animals: a review

“…Ultrastructurally, the site of blistering is the sublamina densa zone (Figure d). In humans, cats, dogs, sheep, cattle and goats with recessive DEB, the anchoring fibrils are scarce and rudimentary. Dystrophic epidermolysis bullosa with similar ultrastructural alterations has also been reported in ostriches, although the mode of inheritance was not determined .…”

Dystrophic epidermolysis bullosa phenotypes in a large consanguineous Tunisian family

“…The variant c.1836G > T RFLP results show that the allele T segregates with the mutation c.7178delT, whereas the well known polymorphism in exon 21, c.2817A > G (p.P939P) [16], detected by the restriction enzyme PvuII, is not in phase with the mutation (Fig. 3).…”