Skin Expression of Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Sibling Patients with Recessive Dystrophic Epidermolysis and Intrafamilial Phenotypic Variation

Abstract

A number of COL7A1 mutations have now been reported in recessive dystrophic epidermolysis bullosa patients, and the analysis of phenotype-genotype correlations showed evidence for interfamilial and intrafamilial phenotypic variability, occurring for the same mutation. Collagenase and stromelysin activities have been found to be overexpressed in skin cultures of some recessive dystrophic epidermolysis bullosa patients, and tissue destruction in the disease process might result from an imbalance of metalloproteinases (MMP) over tissueinhibitor of metalloproteinases (TIMP). So we suspected that the phenotypic variability for the same mutation could be linked to other genetic or environmental factors, as a particular balance between MMP and TIMP. Organ cultures were performed using explants from the skin of three patients from the same family with recessive dystrophic epidermolysis bullosa to reveal and quantify the expression of MMP-1 (collagenase 1), MMP-2 and MMP-9 (gelatinases A and B), MMP-3 (stromelysin 1), TIMP-1, and TIMP-2, and to compare the results with those obtained with two human control skins, with the same experimental conditions. Increased amounts of all metalloproteinases investigated were observed in the skin of the three recessive dystrophic epidermolysis bullosa affected sibling brothers, both in lesioned and in apparently nonlesioned skin, compared with controls. The amounts of MMP-1, MMP-2, MMP-3, and MMP-9 increased particularly in the skin of the more clinically affected patient. Furthermore for this patient we evidenced higher amounts of MMP-1 and also a lower TIMP-1 amount in his unlesioned and lesioned skin compared with the other two affected patients and with healthy control donors. So we can suspect that recessive dystrophic epidermolysis bullosa phenotypic variability could be related to patients' collagenase activity heterogeneity, linked to imbalance between MMP-1 and TIMP-1.

Unraveling the ECM-Immune Cell Crosstalk in Skin Diseases

“…MMPs secreted by immune cells can also influence the recruitment pattern of other immune cells to the injured tissue. Studies have shown that the severity of RDEB is a function of the type of MMP synthesized, its expression level and the balance between MMPs and TIMPs (Bodemer et al, 2003). Interestingly, a SNP (single nucleotide polymorphism) in the MMP1 gene has also been implicated in increasing disease severity by influencing the expression of collagen-VII (Titeux et al, 2008).…”

A novel mutation of COL7A1 in a Chinese DEB‐Pt family and review of the literature

“…We found that the severity and prognosis of the six patients varied widely in this family. This may be related to environmental factors or the expression levels of matrix metalloproteinases (MMP; including MMP1, MMP2, MMP3, and MMP9) in the patient's skin, except for the COL7A1 mutation. This requires further research to arrive at a clear conclusion.…”

Dystrophic Epidermolysis Bullosa: Secondary Disease Mechanisms and Disease Modifiers

“…Further, the nature of amino acid change for a given position is important, as shown by the different phenotypes caused by mutations in the same position (Almaani et al, 2011). Nonetheless, even in patients with the same COL7A1 mutations the phenotypes might differ, as shown by studies in siblings (Hovnanian et al, 1997;Bodemer et al, 2003;Titeux et al, 2008;Odorisio et al, 2014), disclosing that in addition to the causative mutations, other genetic, epigenetic, microenvironmental, and environmental factors contribute to the phenotype. As discussed below, these factors remain limitedly known.…”