Different phenotypes in recessive dystrophic epidermolysis bullosa patients sharing the same mutation in compound heterozygosity with two novel mutations in COL7A1.

Background Dystrophic epidermolysis bullosa (DEB) is a bullous skin disease caused by mutations
in the type VII collagen gene (COL7A1).
Objectives 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 fi 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 fi 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.