Premature termination codons on both alleles of the type VII collagen gene (COL7A1) in three brothers with recessive dystrophic epidermolysis bullosa.

Abstract

Epidermolysis bullosa (EB) is a group of heritable mechano-bullous skin diseases classified into three major categories on the basis of the level of tissue separation within the dermal-epidermal basement membrane zone. In the most severe, dystrophic (scarring) forms of EB, blisters form below the cutaneous basement membrane at the level of the anchoring fibrils, which are composed of type VII collagen. Ultrastructural observations of altered anchoring fibrils and genetic linkage to the type VII collagen locus (COL7A1) have implicated COL7A1 as the candidate gene in the dystrophic forms of EB. We have recently cloned the entire cDNA and the gene for human COL7AL. In this study, we describe distinct mutations in both COL7A1 alleles in three brothers with severe, mutilating recessive dystrophic EB (the Hallopeau-Siemens type, HS-RDEB). The patients are compound heterozygotes for two different mutations, both of which result in a premature termination codon in COL7A1, and the parents were shown to be clinically heterozygous carriers of the respective mutations. Premature termination codons in both alleles of COL7A1 appear to be the underlying cause of severe, recessive dystrophic EB in this family. (J. Clin. Invest. 1995. 95:1328-1334

Renal Amyloidosis in Recessive Dystrophic Epidermolysis bullosa

“…No other relatives were known to have blistering disorders. In these 3 brothers, an analysis of their DNA revealed a distinct mutation of the type VII collagen gene, and this result was reported elsewhere [2]. Blistering had been active and extensive from early infancy, necessitating frequent, often long-term hospital admissions and continuous nursing care as an outpatient.…”

“…any full-length anchoring fibrils [2]. Although it is known that amyloidosis of the AA type (secondary amyloidosis) may complicate dermatoses [3], only 8 sporadic cases of RDEB complicated by secondary amyloidosis have been reported in the English literature [3, 4, 5, 6, 7, 8].…”

Moderation of Phenotypic Severity in Dystrophic and Junctional Forms of Epidermolysis Bullosa Through In-Frame Skipping of Exons Containing Non-Sense or Frameshift Mutations

“…The findings of relatively mild RDEB resulting from a homozygous frameshift mutation in the NC-1 domain, as in the Mexican family studied, however, have not been previously reported. By current paradigms, one would have predicted the three sisters, homozygous for 2470insG in COL7A1, to have severe, generalized, mutilating disease (Hilal et al, 1993;Christiano et al, 1995), yet this was not the case. Indeed, we are aware of other Mexican families with the same mutation with affected individuals now in their 70s (JCSA, unpublished data).…”

Progress in epidermolysis bullosa: Genetic classification and clinical implications

“…In the most severe form, HS-RDEB, the characteristic genetic lesion in COL7A1 is a PTC in both alleles of the affected individual [Christiano et al, 1994c[Christiano et al, , 1995aHovnanian et al, 1994]. The PTCs result in reduced abundance of type VII collagen mRNAs through non-sense-mediated mRNA decay [Christiano et al, 1997], and even if the mutant allele containing the PTC is expressed at reduced level, the translated protein is truncated at its carboxyterminus and therefore unable to assemble into triple helical collagen molecules to form anchoring fibrils (Fig.…”