Background: Dystrophic epidermolysis bullosa (DEB) is a bullous skin disease caused by mutations in the type VII collagen gene (COL7A1).
Objective: To elucidate the mutations shown by two patients with DEB and understand the clinical phenotypes that they displayed.
Methods: We have characterized two patients, one affected by the severe recessive Hallopeau-Siemens variant of DEB (HS-RDEB) and the other by a milder recessive DEB form.
Results: In both patients we identified the R2063W missense mutation. The second mutation, in the HS-RDEB patient, was a novel 344insG, leading to a premature termination codon of translation (PTC) in exon 3, while, in the other patient, it was a novel 4965C-->T transition, which creates a new donor splice site in exon 53. The effect of this anomalous splice site leads to the maturation of a 17-nucleotides-deleted mRNA containing a PTC. In addition to this aberrant transcript, a certain amount of full-length mRNA is also generated from the mutated pre-mRNA through splicing at the canonical site.
Conclusions: In these patients therefore the severity of the phenotype depends on the second mutation. In the patient with the 344insG mutation, leading to a PTC, type VII collagen (COLVII) molecules are exclusively composed of chains containing the R2063W substitution; as a consequence, all anchoring fibrils (AF) are abnormal and the phenotype is severe. In the other patient, the 4965C-->T splicing mutation allows the synthesis of a certain quantity of normal chains and the consequent assembly of partially functional COLVII molecules and AF, thus explaining the mild phenotype.