Exclusion of stromelysin-1, stromelysin-2, interstitial collagenase and fibronectin genes as the mutant loci in a family with recessive epidermolysis bullosa dystrophica and a form of cerebellar ataxia

Abstract

The interstitial collagenase gene (CLG), one of the main candidates in severe generalized recessive epidermolysis bullosa dystrophica (SGREBD), is closely linked to the stromelysin-1 (STMY1) and stromelysin-2 (STMY2) genes. These three loci map on chromosome 11 (q21-q22.3), where they constitute a cluster of genes coding for metalloproteinases involved in the degradation of the extracellular matrix (ECM). A recessive form of cerebellar ataxia of post-puberal onset (CLA1) has also been assigned to chromosome 11 (q14-q21). Since useful restriction fragment length polymorphisms (RFLPs) for the CLG gene are not available, we have studied the inheritance of the marker TaqI RFLP of the STMY1 gene in a North Italian family with a child affected by SGREBD, and his two sisters showing cerebellar ataxia (CA) of post-puberal onset. We have also studied the MspI RFLP of the fibronectin gene (FN1), which is located on chromosome 2q34-q36, and which codes for non-collagenous matrix proteins. Since we did not observe the segregation of the pathological phenotypes with STMY1 and FN1 RFLPs, we excluded the involvement of these genes in both the SGREBD and CA present in this family. The exclusion of the STMY1 gene indicates that the mutation causing SGREBD cannot be located in the CLG and/or STMY2 genes because of their proximity to the STMY1 locus. These data also indicate that the CA form here reported is not attributable to alterations in regions close to the collagenase cluster on chromosome 11.

A frequent functional SNP in theMMP1promoter is associated with higher disease severity in recessive dystrophic epidermolysis bullosa

“…Among possible candidate modifier genes of RDEB, MMP1 (MIM] 120353), encoding the matrix metalloproteinase type I (MMP1), was first implicated in RDEB [Bauer and Eisen, 1978;Stricklin et al, 1982] before its causative role in the disease was excluded by linkage analysis [Colombi et al, 1992;Hovnanian et al, 1991]. MMP1 is the most ubiquitous member of a family of zinc metallo-endopeptidases (matrix metalloproteinases, MMPs) which degrade and remove extracellular matrix molecules from tissues and have been involved in tissue remodeling, wound healing, and cancer invasiveness in particular [Chakraborti et al, 2003].…”

Three homozygous PTC mutations in the collagen type VII gene of patients affected by recessive dystrophic epidermolysis bullosa: Analysis of transcript levels in dermal fibroblasts

“…The patient is the son of first-cousins parents with an inbreed pedigree. In this family, previously described by Colombi et al [1992], the parents and the two sisters of the propositus are not affected by HS-RDEB; a brother, affected by HS-RDEB, died at the age of 3 months; and two pregnancies resulted in spontaneous abortions. This family has been residing in northern Italy for several generations.…”

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

“…Some authors have reported overexpression of collagenase and stromelysin gene in some, but not all, cell lines (Winberg et al, 1989;Sugawara et al, 1993). Clearly RDEB is caused by a defect in the type VII collagen gene, and not in the collagenase and stromelysin gene (Hovnanian et al, 1991;Colombi et al, 1992). Arbiser et al (1998), however, demonstrated that patients with RDEB have elevated levels of b ¢broblast growth factor, which may contribute to increased ¢broblast collagenase expression, and Sato et al (1995) reported that interleukin-1b added in the culture conditioned medium of RDEB ¢broblasts enhanced collagenase production of these cells.…”