[en] Ehlers-Danlos syndrome (EDS) type VIIC, or dermatosparactic type, is a recessively inherited connective tissue disorder characterized, among other symptoms, by an extreme skin fragility resulting from mutations inactivating ADAMTS-2, an enzyme excising the aminopropeptide of procollagens type I, II, and III. All previously described mutations create premature stop codons leading to a marked reduction in the level of mRNA. In this study, we analyzed the ADAMTS2 cDNA sequences from five patients displaying clinical and/or biochemical features consistent with a diagnosis of either typical or potentially mild form of EDS type VIIC. Three different alterations were detected in the two patients with typical EDS type VIIC. The first patient was homozygous for a genomic deletion causing an in-frame skipping of exons 3-5 in the transcript. In the second patient, the allele inherited from the mother lacks exon 3, generating a premature stop codon, whereas the paternal allele has a genomic deletion resulting in an in-frame skipping of exons 14-16 at the mRNA level. Although the exons 3-5 or 14-16 encode protein domains that have not been previously recognized as crucial for ADAMTS-2 activity, the aminoprocollagen processing was strongly impaired in vitro and in vivo, providing evidence for the requirement of these domains for proper enzyme function. The three other patients with a phenotype with some resemblance to EDS type VIIC only had silent and functionally neutral variations also frequently found in a normal population.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Colige, Alain ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire de Biologie des Tissus Conjonctifs
Nuytinck, Lieve; University ogf Ghent > Universitair Ziekenhuis > Centrum voor Medische Genetica
Hausser, Ingrid; University of Heidelberg, Germany > Dept of Dermatology > Electron Microscopic Laboratory
van Essen, Anthonie J; University Hospital Groningen, the Netherlands > Dpt of Clinical Genetics
Thiry, Marc ; Université de Liège - ULiège > Département des sciences de la vie > Biologie cellulaire
Herens, Christian ; Centre Hospitalier Universitaire de Liège - CHU > Génétique
Ades, Lesley C; University of Sidney > Dept of Clinical Genetics > The Children Hospital
Malfait, Fransiska; University of Ghent > Center for Medical Genetics
Paepe, Anne De; Ghent for Medical Genetics > Center for Medical Genetics
Franck, Peter; University Hospital, Freiburg, Germany > Center for Paediatrics and Youth Medicine
Wolff, Gerhard; University of Freiburg - Germany > Dpt of Pediatrics
Oosterwijk, Jan C; University Hospital Groningen, the Netherlands > Dpt of Clinical Genetics
Smitt, J H Sillevis; University of Amsterdam > Dept of Dermatology > Academic Medical Center
Lapiere, Charles M; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire de Biologie des Tissus Conjonctifs
Nusgens, Betty ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire de Biologie des Tissus Conjonctifs
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