In this Issue: Secondary Modifiers and the Phenotypic Variability of Junctional Epidermolysis Bullosa
In this issue Professor Dédée Murrell, Sydney, Australia, and collaborators (Dang et al. p. 438–448) report on phenotypic variability in junctional epidermolysis bullosa with pyloric atresia (JEB-PA). They conclude that environmental factors and genetic modifiers must contribute to the clinical manifestations of this disease, which is caused by mutations in the ITGB4 gene.
JEB-PA is an autosomal recessive blistering skin disorder that includes lethal and non-lethal variants. The reasons for variable severity have remained elusive, since all patients seem to have mutations in the integrin alpha 6 or integrin beta 4 genes, ITGA6 and ITGB4. In this study, three families were analysed and their ITGB4 mutations identified. One family was particularly interesting, since it had one sibling with and another without pyloric atresia (PA), both with the same homozygous ITGB4 mutation. The study carefully compares clinical phenotypes using immunofluorescence mapping and ultra-structural analysis of skin biopsies. The observations extend our knowledge on the integrin mutations and help evaluate the genotype/phenotype correlations in JEB-PA. It becomes evident that environmental, epigenetic or other genetic modifying factors must play a role in this form of epidermolysis bullosa (EB), since the clinical variability cannot be explained alone on the basis of the mutated integrin beta 4 subunit.
Interestingly, a recent paper (1) described a genetic modifier for another EB type, dystrophic EB (DEB). In this case, a polymorphism in the gene for matrix metalloproteinase-1 (MMP-1) seems to influence the presence of collagen VII protein, the major anchoring fibril component, in the skin of patients with DEB. The polymorphism leads to increased MMP-1 activity, which in turn, degrades normal and mutated collagen VII in the skin. Patients with recessive DEB, who already have reduced amounts of mutated collagen VII in the skin, are particularly sensitive to this additional modulation. The presence of the polymorphism and, thus, more active MMP-1, leads to loss of anchoring fibril function and worsens the dysadhesion in the skin. Subsequently, skin blistering and scarring are enhanced, and the clinical phenotypes become more severe.
In analogy to this, the present paper by Dang et al. suggests that secondary modifiers also determine the development of pyloric atresia in conjunction with ITGB4 mutations. It will be exciting to discover the identity of such genetic modifiers.
1. Titeux M, Pendaries V, Tonasso L, Décha A, Bodemer C, Hovnanian A. A frequent functional SNP in the MMP1 promoter is associated with higher disease severity in recessive dystrophic epidermolysis bullosa. Hum Mutat 2008; 29: 267–276.