Alternative titles; symbols
ORPHA: 230857;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.33 | Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 | 619115 | Autosomal dominant | 3 | COL1A1 | 120150 |
A number sign (#) is used with this entry because of evidence that combined osteogenesis imperfecta and Ehlers-Danlos syndrome-1 (OIEDS1) is caused by heterozygous mutation in the COL1A1 gene (120150) on chromosome 17q21.
Combined osteogenesis imperfecta and Ehlers-Danlos syndrome-1 (OIEDS1) is an autosomal dominant generalized connective tissue disorder characterized by features of both osteogenesis imperfecta (bone fragility, long bone fractures, blue sclerae) and Ehlers-Danlos syndrome (joint hyperextensibility, soft and hyperextensible skin, abnormal wound healing, easy bruising, vascular fragility) (summary by Cabral et al., 2007; Malfait et al., 2013).
Genetic Heterogeneity of Combined Osteogenesis Imperfecta and Ehlers-Danlos Syndrome
Also see OIEDS2 (619120), caused by mutation in the COL1A2 gene (120160) on chromosome 7q21.
Cabral et al. (2005) reported 7 children with features of OI type III or type VI who also had severe large and small joint laxity and early progressive scoliosis.
Cabral et al. (2007) reported a small pedigree with an OIEDS phenotype characterized by a moderately decreased DEXA z-score (-1.3 to -2.6), long bone fractures, and large joint hyperextensibility. At age 12 years, the proband had experienced 4 fractures in 1 year, 2 involving the tibiae and 2 involving small bones, as well as significant large joint laxity. The proband, his 43-year-old father, and his 11-year-old brother had features of both OI and EDS. Bone density based on DEXA studies put them into the osteopenic and moderately osteoporotic range. All 3 patients had fractures in childhood and light blue sclerae. Growth and body habitus were in the normal range (10th centile in the adult), with normal arm span:height and upper segment:lower segment proportions. Skin was unremarkable without increased extensibility, atrophic scars, increased transparency, or easy bruisability. Another brother had a normal physical examination at 6 months of age, despite carrying the same COL1A1 mutation as his father and brothers.
Malfait et al. (2013) reported a cohort of 7 patients with a clinical diagnosis of EDS who showed subtle signs of OI. The patients presented with severe joint hyperlaxity, soft and hyperextensible skin, abnormal wound healing, and easy bruising. Some had signs of vascular fragility, including an epidural hematoma with intraspinal hemorrhage following relatively mild trauma in a 5-year-old and a massive intracranial bleed in a newborn. Transmission electron microscopy, performed on one of the patients at age 37 years, showed lowered collagen fibril density in the dermis. Subtle signs of OI included blue sclerae, relatively short stature, and osteopenia or fractures. One patient had an atrial septal defect and another had aortic dilatation. The authors emphasized the importance of recognizing this phenotype for accurate genetic counseling, clinical management, and disease surveillance.
Symoens et al. (2017) described a patient with clinical manifestations of EDS, including fragile skin, easy bruising, and recurrent luxations, as well as fractures and slightly blue sclerae consistent with mild OI. Biochemical analysis of dermal collagens showed slightly overmodified type I collagen.
The transmission pattern of OIEDS1 in the families reported by Cabral et al. (2005) was consistent with autosomal dominant inheritance.
In 7 children with combined osteogenesis imperfecta and Ehlers-Danlos syndrome-1, Cabral et al. (2005) identified heterozygous mutations in the COL1A1 gene (see, e.g., 120150.0064). All of the mutations occurred in the first 90 residues of the helical region of alpha-1(I) collagen. The mutations prevented or delayed removal of the procollagen N-propeptide by purified N-proteinase (ADAMTS2; 604539) in vitro and in pericellular assays. The mutant pN-collagen that resulted was efficiently incorporated into matrix by cultured fibroblasts and osteoblasts and was prominently present in newly incorporated and immaturely cross-linked collagen. Dermal collagen fibrils had significantly reduced cross-sectional diameters, corroborating incorporation of pN-collagen into fibrils in vivo. The mutations disrupted a distinct folding region of high thermal stability in the first 90 residues at the amino end of type I collagen and altered the secondary structure of the adjacent N-proteinase cleavage site. Thus, these mutations are directly responsible for the bone fragility of OI and indirectly responsible for EDS symptoms, by interference with N-propeptide removal.
In 4 patients in a small pedigree with OIEDS, Cabral et al. (2007) identified heterozygosity for a c.3196C-T transition in the COL1A1 gene, resulting in an arg888-to-cys substitution (R888C; 120150.0071) in the Y position of one of the Gly-X-Y triplets that compose the collagen helix. The substitution in the Y position was shown to result in less delay in helix formation than would have been expected for a glycine substitution. Disulfide-bonded dimers of alpha(I) chains formed inefficiently in helices with 2 mutant chains; however, secretion from cells was normal. Formation of disulfide dimers at position 888 resulted in helix kinking, with resulting decreased helix stability and propagation of altered secondary structure along the remaining helix.
Malfait et al. (2013) sequenced the COL1A1 and COL1A2 genes in 7 patients with OIEDS and identified heterozygous mutations in the most N-terminal part of the type I collagen helix (2 in COL1A1 and 5 in COL1A2), close to the procollagen type I N-proteinase cleavage site, in all patients. Both mutations in COL1A1 were missense (G188D, 120150.0072 and G203C); 3 of the mutations in COL1A2 were exon skipping and 2 were missense. The mutations affected the rate of type I collagen N-propeptide cleavage and disturbed normal collagen fibrillogenesis.
By Sanger sequencing in a patient with OIEDS, Symoens et al. (2017) identified an in-frame 9-bp deletion in exon 44 of the COL1A1 gene (c.3150_3158del; 120150.0073), resulting in deletion of 3 amino acids in the collagen triple helix. The mutation was found to be present in mosaic state, which the authors concluded was responsible for the mild symptoms in the patient.
Chen et al. (2014) reported a mouse model with a heterozygous T-C transition at a splice donor site of the Col1a1 gene, resulting in skipping of exon 9 and a predicted 18-amino acid deletion within the N-terminal region of the triple helical domain (Col1a1(Jrt)/+). Heterozygous mice are smaller than normal and have low bone mineral density and mechanically weak, fracture-prone bones, consistent with an osteogenesis imperfecta phenotype. The number of bone marrow stromal osteoprogenitors was normal, but mineralization was decreased in cultures from the heterozygous mice compared to wildtype mice. The heterozygous mice also had traits associated with Ehlers-Danlos syndrome, including reduced tensile properties of the skin, frayed tail tendon, and, in a third of the mice, noticeable curvature of the spine. The authors noted that this was the first reported animal model of the OIEDS syndrome.
Cabral, W. A., Makareeva, E., Colige, A., Letocha, A. D., Ty, J. M., Yeowell, H. N., Pals, G., Leikin, S., Marini, J. C. Mutations near amino end of alpha-1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing. J. Biol. Chem. 280: 19259-19269, 2005. [PubMed: 15728585] [Full Text: https://doi.org/10.1074/jbc.M414698200]
Cabral, W. A., Makareeva, E., Letocha, A. D., Scribanu, N., Fertala, A., Steplewski, A., Keene, D. R., Persikov, A. V., Leikin, S., Marini, J. C. Y-position cysteine substitution in type I collagen (alpha-1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype. Hum. Mutat. 28: 396-405, 2007. [PubMed: 17206620] [Full Text: https://doi.org/10.1002/humu.20456]
Chen, F., Guo, R., Itoh, S., Moreno, L., Rosenthal, E., Zappitelli, T., Zirngibl, R. A., Flenniken, A., Cole, W., Grynpas, M., Osborne, L. R., Vogel, W., Adamson, L., Rossant, J., Qubin, J. E. First mouse model for combined osteogenesis imperfecta and Ehlers-Danlos syndrome. J. Bone Miner. Res. 29: 1412-1423, 2014. [PubMed: 24443344] [Full Text: https://doi.org/10.1002/jbmr.2177]
Malfait, F., Symoens, S., Goemans, N., Gyftodimou, Y., Holmberg, E., Lopez-Gonzalez, V., Mortier, G., Nampoothiri, S., Petersen, M. B., De Paepe, A. 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 J. Rare Dis. 8: 78, 2013. Note: Electronic Article. [PubMed: 23692737] [Full Text: https://doi.org/10.1186/1750-1172-8-78]
Symoens, S., Steyaert, W., Demuynck, L., De Paepe, A., Diderich, K. E. M., Malfait, F., Coucke, P. J. Tissue-specific mosaicism for a lethal osteogenesis imperfecta COL1A1 mutation causes mild OI/EDS overlap syndrome. Am. J. Med. Genet. 173: 1047-1050, 2017. [PubMed: 28261977] [Full Text: https://doi.org/10.1002/ajmg.a.38135]