title: A frequent functional SNP in the MMP1 promoter is associated with higher disease severity in recessive dystrophic epidermolysis bullosa.
abstract: Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in the COL7A1 gene encoding type VII collagen. Variations in severity between the different clinical forms of RDEB likely depend on the nature and location of COL7A1 mutations, but observed intrafamilial phenotypic variations suggest additional genetic and/or environmental factors. Candidate modifier genes include MMP1, encoding matrix metalloproteinase 1, the first gene implicated in RDEB before its primary role in the disease was excluded. Type VII collagen is a substrate of MMP1 and an imbalance between its synthesis and degradation could conceivably worsen the RDEB phenotype. Here, we studied a previously described family with three affected siblings of identical COL7A1 genotype but displaying great sibling-to-sibling variations in disease severity. RDEB severity did not correlate with type VII collagen synthesis levels, but with protein levels at the dermal-epidermal junction, suggesting increased degradation by metalloproteinases. This was supported by the presence of increased transcript and active MMP1 levels in the most severely affected children, who carried a known SNP (1G/2G) in the MMP1 promoter. This SNP creates a functional Ets binding site resulting in transcriptional upregulation. We next studied a French cohort of 31 unrelated RDEB patients harboring at least one in-frame COL7A1 mutation, ranging from mild localized RDEB to the severe Hallopeau-Siemens form. We found a strong genetic association between the 2G variant and the Hallopeau-Siemens disease type (odds ratio: 73.6). This is the first example of a modifier gene in RDEB and has implications for its prognosis and possible new treatments.
authors.affiliation: INSERM, U563, Toulouse, France.
authors.forename: Matthias
authors.initials: M
authors.lastname: Titeux
authors.forename: Valérie
authors.initials: V
authors.lastname: Pendaries
authors.forename: Laure
authors.initials: L
authors.lastname: Tonasso
authors.forename: Audrey
authors.initials: A
authors.lastname: Décha
authors.forename: Christine
authors.initials: C
authors.lastname: Bodemer
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
mesh_terms: D000293:Adolescent; D000328:Adult; D001665:Binding Sites; D002478:Cells, Cultured; D015331:Cohort Studies; D024143:Collagen Type VII / Q000378:metabolism; D016108:Epidermolysis Bullosa Dystrophica / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005602:France; D015971:Gene Expression Regulation, Enzymologic; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D024143:Collagen Type VII; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D020781:Matrix Metalloproteinase 1