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Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome overlap syndrome

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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. Conclusion: 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.
Keywords
Osteogenesis Imperfecta, Ehlers-Danlos syndrome, Type I collagen, Arterial fragility, Genotype, Phenotype, PROCOLLAGEN N-PROTEINASE, ARTHROCHALASIA TYPE, COL1A2, CHAIN, VIIA, ADULTHOOD, DOMAIN, DEFECT, GENE, END

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MLA
Malfait, Fransiska et al. “Helical Mutations in Type I Collagen That Affect the Processing of the Amino-propeptide Result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome Overlap Syndrome.” ORPHANET JOURNAL OF RARE DISEASES 8 (2013): n. pag. Print.
APA
Malfait, Fransiska, Symoens, S., Goemans, N., Gyftodimou, Y., Holmberg, E., Lopez-Gonzalez, V., Mortier, G., et al. (2013). Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome overlap syndrome. ORPHANET JOURNAL OF RARE DISEASES, 8.
Chicago author-date
Malfait, Fransiska, Sofie Symoens, Nathalie Goemans, Yolanda Gyftodimou, Eva Holmberg, Vanesa Lopez-Gonzalez, Geert Mortier, Sheela Nampoothiri, Michael Bjorn Petersen, and Anne De Paepe. 2013. “Helical Mutations in Type I Collagen That Affect the Processing of the Amino-propeptide Result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome Overlap Syndrome.” Orphanet Journal of Rare Diseases 8.
Chicago author-date (all authors)
Malfait, Fransiska, Sofie Symoens, Nathalie Goemans, Yolanda Gyftodimou, Eva Holmberg, Vanesa Lopez-Gonzalez, Geert Mortier, Sheela Nampoothiri, Michael Bjorn Petersen, and Anne De Paepe. 2013. “Helical Mutations in Type I Collagen That Affect the Processing of the Amino-propeptide Result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome Overlap Syndrome.” Orphanet Journal of Rare Diseases 8.
Vancouver
1.
Malfait F, Symoens S, Goemans N, Gyftodimou Y, Holmberg E, Lopez-Gonzalez V, et al. Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome overlap syndrome. ORPHANET JOURNAL OF RARE DISEASES. 2013;8.
IEEE
[1]
F. Malfait et al., “Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome overlap syndrome,” ORPHANET JOURNAL OF RARE DISEASES, vol. 8, 2013.
@article{4106937,
  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.
Conclusion: 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.},
  articleno    = {78},
  author       = {Malfait, Fransiska and Symoens, Sofie and Goemans, Nathalie and Gyftodimou, Yolanda and Holmberg, Eva and Lopez-Gonzalez, Vanesa and Mortier, Geert and Nampoothiri, Sheela and Petersen, Michael Bjorn and De Paepe, Anne},
  issn         = {1750-1172},
  journal      = {ORPHANET JOURNAL OF RARE DISEASES},
  keywords     = {Osteogenesis Imperfecta,Ehlers-Danlos syndrome,Type I collagen,Arterial fragility,Genotype,Phenotype,PROCOLLAGEN N-PROTEINASE,ARTHROCHALASIA TYPE,COL1A2,CHAIN,VIIA,ADULTHOOD,DOMAIN,DEFECT,GENE,END},
  language     = {eng},
  pages        = {10},
  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},
  url          = {http://dx.doi.org/10.1186/1750-1172-8-78},
  volume       = {8},
  year         = {2013},
}

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