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

Anne De Paepe⁸  Michael Bjorn Petersen⁶  Sheela Nampoothiri⁴  Geert Mortier²  Vanesa López-González¹  Eva Holmberg⁷  Yolanda Gyftodimou⁵  Nathalie Goemans³  Sofie Symoens⁸  Fransiska Malfait⁸ 

[1] Unidad de Genetica Medica, Servicio de Pediatria, Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain;Department of Medical Genetics, Antwerp University Hospital, University of Antwerp, 2650 Edegem and Ghent University, Ghent, Belgium;Child Neurology, University Hospitals Leuven, Leuven, Belgium;Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara PO, Cochin, Kerala, India;Department of Genetics, Institute of Child Health, Athens, 11527, Greece;Department of Clinical Genetics, Aalborg University Hospital, Aalborg, 9000, Denmark;Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, SE-413 45, Sweden;Center for Medical Genetics, Ghent University Hospital, De Pintelaan 85, Ghent 9000, Belgium

关键词: Phenotype;    Genotype;    Arterial fragility;    Type I collagen;    Osteogenesis Imperfecta;    Ehlers-Danlos syndrome;   

Others  :  863741
DOI  :  10.1186/1750-1172-8-78

 received in 2013-02-01, accepted in 2013-05-05,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Malfait et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Dalgleish R: The Human Collagen Mutation Database 1998. Nucleic Acids Res 1998, 26:253-255.
• [2]Forlino A, Cabral WA, Barnes AM, Marini JC: New perspectives on osteogenesis imperfecta. Nat Rev Endocrinol 2011, 7:540-557.
• [3]Marini JC, Forlino A, Cabral WA, Barnes AM, San Antonio JD, Milgrom S, Hyland JC, Korkko J, Prockop DJ, De Paepe A, Coucke P, Symoens S, Glorieux FH, Roughley PJ, Lund AM, Kuurila-Svahn K, Hartikka H, Cohn DH, Krakow D, Mottes M, Schwarze U, Chen D, Yang K, Kuslich C, Troendle J, Dalgleish R, Byers PH: Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat 2007, 28:209-221.
• [4]Byers PH, Duvic M, Atkinson M, Robinow M, Smith LT, Krane SM, Greally MT, Ludman M, Matalon R, Pauker S, Quanbeck D, Schwarze U: Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen. Am J Med Genet A 1997, 72:94-105.
• [5]Giunta C, Chambaz C, Pedemonte M, Scapolan S, Steinmann B: The arthrochalasia type of Ehlers-Danlos syndrome (EDS VIIA and VIIB): the diagnostic value of collagen fibril ultrastructure. Am J Med Genet A 2008, 146A:1341-1346.
• [6]Klaassens M, Reinstein E, Hilhorst-Hofstee Y, Schrander J, Malfait F, Staal H, Ten Have L, Blaauw J, Roggeveen H, Krakow D, De Paepe A, van Steensel M, Pals G, Graham J, Schrander-Stumpel C: Ehlers-Danlos arthrochalasia type (VIIA-B) - expanding the phenotype: from prenatal life through adulthood. Clin Genet 2012, 82:121-130.
• [7]Cabral WA, Makareeva E, Colige A, Letocha AD, Ty JM, Yeowell HN, Pals G, Leikin S, Marini JC: Mutations near amino end of α1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos Sydrome by interference with N-propeptide processing. J Biol Chem 2005, 280(19):19259-19269.
• [8]Sippola M, Kaffe S, Prockop DJ: A heterozygous defect for structurally altered pro-α2 chain of type I procollagen in a mild variant of osteogenesis imperfecta. The altered structure decreases the thermal stability of procollagen and makes it resistant to procollagen N-proteinase. J Biol Chem 1984, 259:14094-14100.
• [9]Raff ML, Craigen WJ, Smith LT, Keene DR, Byers PH: Partial COL1A2 gene duplication produces features of osteogenesis imperfecta and Ehlers-Danlos syndrome type VII. Hum Genet 2000, 106:19-28.
• [10]Nicholls AC, Oliver J, Renouf DV, Heath DA, Pope FM: The molecular defect in a family with mild atypical osteogenesis imperfecta and extreme joint hypermobility: exon skipping caused by an 11-bp deletion from an intron in one COL1A2 allele. Hum Genet 1992, 88:627-633.
• [11]Feshchenko S, Brinckmann J, Lehmann HW, Koch HG, Muller PK, Kugler S: Identification of a new heterozygous point mutation in the COL1A2 gene leading to skipping of exon 9 in a patient with joint laxity, hyperextensibility of skin and blue sclerae. Hum Mutat 1998, 12:138.
• [12]Dombrowski KE, Vogel BE, Prockop DJ: Mutations that alter the primary structure of type I procollagen have long-range effects on its cleavage by procollagen N-proteinase. Biochemistry 1989, 28:7107-7112.
• [13]Makareeva E, Cabral WA, Marini JC, Leikin S: Molecular mechanism of α1(I)-osteogenesis imperfecta/Ehlers-Danlos syndrome: unfolding of an N-anchor domain at the N-terminal end of the type I collagen triple helix. J Biol Chem 2006, 281:6463-6470.
• [14]Mayer SA, Rubin BS, Starman BJ, Byers PH: Spontaneous multivessel cervical artery dissection in a patient with a substitution of alanine for glycine (G13A) in the α1 (I) chain of type I collagen. Neurology 1996, 47:552-556.
• [15]Malfait F, Symoens S, De Backer J, Hermanns-Lé T, Sakalihasan N, Lapière CM, Coucke P, De Paepe A: Three arginine to cysteine substitutions in the pro-α(I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood. Hum Mutat 2007, 28:387-395.
• [16]Faqeih E, Roughley P, Glorieux FH, Rauch F: Osteogenesis imperfecta type III with intracranial hemorrhage and brachydactyly associated with mutations in exon 49 of COL1A2. Am J Med Genet A 2009, 149A:461-465.
• [17]Yoneyama T, Kasuya H, Onda H, Akagawa H, Hashiguchi K, Nakajima T, Hori T, Inoue I: Collagen type I α2 (COL1A2) is the susceptible gene for intracranial aneurysms. Stroke 2004, 35:443-448.