title: Novel types of mutation responsible for the dermatosparactic type of Ehlers-Danlos syndrome (Type VIIC) and common polymorphisms in the ADAMTS2 gene.
abstract: 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.
authors.affiliation: Laboratory of Connective Tissues Biology, GIGA Research Center, University of Liège, Liège, Belgium. acolige@ulg.ac.be
authors.forename: Alain
authors.initials: A
authors.lastname: Colige
authors.forename: Lieve
authors.initials: L
authors.lastname: Nuytinck
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.forename: Anthonie J
authors.initials: AJ
authors.lastname: van Essen
authors.forename: Marc
authors.initials: M
authors.lastname: Thiry
authors.forename: Christian
authors.initials: C
authors.lastname: Herens
authors.forename: Lesley C
authors.initials: LC
authors.lastname: Adès
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
authors.forename: Anne De
authors.initials: AD
authors.lastname: Paepe
authors.forename: Peter
authors.initials: P
authors.lastname: Franck
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolff
authors.forename: Jan C
authors.initials: JC
authors.lastname: Oosterwijk
authors.forename: J H Sillevis
authors.initials: JH
authors.lastname: Smitt
authors.forename: Charles M
authors.initials: CM
authors.lastname: Lapière
authors.forename: Betty V
authors.initials: BV
authors.lastname: Nusgens
mesh_terms: D051722:ADAM Proteins; D000071096:ADAMTS Proteins; D000071121:ADAMTS4 Protein; D000818:Animals; D002478:Cells, Cultured; D002675:Child, Preschool; D018389:Codon, Nonsense; D020405:Dermis / Q000166:cytology; D004535:Ehlers-Danlos Syndrome / Q000145:classification / Q000235:genetics* / Q000473:pathology; D005347:Fibroblasts / Q000648:ultrastructure; D006801:Humans; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D011110:Polymorphism, Genetic; D011348:Procollagen N-Endopeptidase / Q000737:chemistry / Q000235:genetics*; D017434:Protein Structure, Tertiary
chemical_list: D018389:Codon, Nonsense; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C000609307:ADAMTS2 protein, human; C000609308:Adamts2 protein, mouse; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein