title: Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome overlap syndrome.
abstract: BACKGROUND
  Whereas mutations affecting the helical domain of type I procollagen classically cause Osteogenesis Imperfecta (OI), helical mutations near the amino (N)-proteinase cleavage site have been suggested to result in a mixed OI/Ehlers-Danlos syndrome (EDS)-phenotype.
  
  
  METHODS
  We performed biochemical and molecular analysis of type I (pro-) collagen in a cohort of seven patients referred with a clinical diagnosis of EDS and showing only subtle signs of OI. Transmission electron microscopy of the dermis was available for one patient.
  
  
  RESULTS
  All of these patients harboured a COL1A1 / COL1A2 mutation residing within the most N-terminal part of the type I collagen helix. These mutations affect the rate of type I collagen N-propeptide cleavage and disturb normal collagen fibrillogenesis. Importantly, patients with this type of mutation do not show a typical OI phenotype but mainly present as EDS patients displaying severe joint hyperlaxity, soft and hyperextensible skin, abnormal wound healing, easy bruising, and sometimes signs of arterial fragility. In addition, they show subtle signs of OI including blue sclerae, relatively short stature and osteopenia or fractures.
  
  
  CONCLUSIONS
  Recognition of this distinct phenotype is important for accurate genetic counselling, clinical management and surveillance, particularly in relation to the potential risk for vascular rupture associated with these mutations. Because these patients present clinical overlap with other EDS subtypes, biochemical collagen analysis is necessary to establish the correct diagnosis.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 85, Ghent 9000, Belgium. Fransiska.Malfait@Ugent.be
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
authors.forename: Sofie
authors.initials: S
authors.lastname: Symoens
authors.forename: Nathalie
authors.initials: N
authors.lastname: Goemans
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Gyftodimou
authors.forename: Eva
authors.initials: E
authors.lastname: Holmberg
authors.forename: Vanesa
authors.initials: V
authors.lastname: López-González
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.forename: Sheela
authors.initials: S
authors.lastname: Nampoothiri
authors.forename: Michael Bjorn
authors.initials: MB
authors.lastname: Petersen
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
mesh_terms: D000328:Adult; D002648:Child; D024042:Collagen Type I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011347:Procollagen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D010446:Peptide Fragments; D011347:Procollagen