Partial COL1A2 gene duplication produces features of osteogenesis imperfecta and Ehlers-Danlos syndrome type VII

Raff, M.L.; Craigen, W.J.; Smith, L.T.; Keene, D.R.; Byers, Peter H.

doi:10.1007/s004390051004

Cited by 36 publications

(19 citation statements)

References 28 publications

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“…Here, we report a large in frame duplication of COL4A5 resulting in a 1054 amino acid longer a5(IV) chain (an increase of ∼65% in the length of the triple helical domain of the chain) which, surprisingly, is still able to assemble with a3(IV) and a4(IV) into the GBM collagen network, as shown by the normal expression of the a5(IV) chain in the Tahitian patients' kidneys. A similarly mutated a2(I) chain with an aberrantly long, albeit shorter than that we report here, triple helical domain was shown to be incorporated into fibrillar procollagen molecules [30]. Additionally, the fact that the triple helical domains of type IV collagen molecules naturally comprise frequent noncollagenous interruptions, thought to play a role in flexibility [31], may explain why the insertion of a short noncollagenous sequence does not affect the assembly of the mutated chain.…”

Section: Discussionmentioning

confidence: 73%

A large tandem duplication within the COL4A5 gene is responsible for the high prevalence of Alport syndrome in French Polynesia

Arrondel¹,

Deschênes²,

Meur³

et al. 2004

Kidney International

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A large tandem duplication within the COL4A5 gene is responsible for the high prevalence of Alport syndrome in French Polynesia. Background. The prevalence of X-linked Alport syndrome, a progressive inherited nephropathy associated with mutations in the type IV collagen gene COL4A5, is remarkably high in French Polynesia. Methods. A vast clinical, genealogic, and molecular study was undertaken in Polynesia, based on public records, patients' interviews, linkage analysis, and mutation screening. Results and Conclusions. We show that the high frequency of Alport syndrome in this region is due to a founder mutation that occurred onto a common haplotype shared by affected and unaffected individuals, the presence of which precludes indirect molecular diagnosis. We have characterized the mutation as a tandem duplication of 35 COL4A5 exons, resulting in a approximately 65% increase in the length of the collagenous domain of the alpha 5(IV) chain, which is still able to assemble into type IV collagen network as shown by immunofluorescence analysis. That mutation is associated with severe and highly penetrant ocular symptoms and with uniformly thin glomerular basement membrane (GBM) in male adult patients. However, the rate of progression of the renal disease is very variable from one male patient to another, demonstrating the importance of strong modifier factors. Our results suggest that the 20% to 50% of "missing"COL4A5 mutations in X-linked Alport syndrome may be rearrangements similar to that reported here, which was not detectable by sequencing of either individual COL4A5 exons or overlapping cDNA fragments. Finally, we provide the basis for a polymerase chain reaction (PCR) assay that accurately identifies female carriers and allows adequate genetic counseling in this population.

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Section: Discussionmentioning

confidence: 73%

A large tandem duplication within the COL4A5 gene is responsible for the high prevalence of Alport syndrome in French Polynesia

Arrondel¹,

Deschênes²,

Meur³

et al. 2004

Kidney International

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“…The phenotype of ␣2(I)-OI/EDS patients was reported to be generally consistent with EDSVIIA/B. Their dermal fibrils were not studied except for one unusual case of a large duplication of exons 12-32 in COL1A2 (23). The latter patient had EDS VIIA/B phenotype with bilateral congenital hip dislocation but thin, rounded fibrils with uniform diameters similar to ␣1(I)-OI/EDS.…”

Section: A Single Mutant Chain Is Not Sufficient Tomentioning

confidence: 99%

Molecular Mechanism of α1(I)-Osteogenesis Imperfecta/Ehlers-Danlos Syndrome

Makareeva

Cabral

Marini

et al. 2006

Journal of Biological Chemistry

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We demonstrate that 85 N-terminal amino acids of the ␣1(I) chain participate in a highly stable folding domain, acting as the stabilizing anchor for the amino end of the type I collagen triple helix. This anchor region is bordered by a microunfolding region, 15 amino acids in each chain, which include no proline or hydroxyproline residues and contain a chymotrypsin cleavage site. Glycine substitutions and amino acid deletions within the N-anchor domain induce its reversible unfolding above 34°C. The overall triple helix denaturation temperature is reduced by 5-6°C, similar to complete N-anchor removal. N-propeptide partially restores the stability of mutant procollagen but not sufficiently to prevent N-anchor unfolding and a conformational change at the N-propeptide cleavage site. The ensuing failure of N-proteinase to cleave at the misfolded site leads to incorporation of pN-collagen into fibrils. Similar, but weaker, effects are caused by G88E substitution in the adjacent triplet, which appears to alter N-anchor structure as well. As in Ehlers-Danlos syndrome (EDS) VIIA/B, fibrils containing pNcollagen are thinner and weaker causing EDS-like laxity of large and small joints and paraspinal ligaments. However, distinct structural consequences of N-anchor destabilization result in a distinct ␣1(I)-osteogenesis imperfecta (OI)/EDS phenotype.Mature type I collagen is a heterotrimer of two ␣1(I) and one ␣2(I) chains folded into a 300-nm-long triple helix with short, unstructured telopeptides at the N-and C-terminal ends. The distinguishing feature of the collagen triple helix is an obligatory Gly residue in every third position on each chain. Collagen precursor (procollagen) is synthesized and folded within the rough endoplasmic reticulum. It is secreted by cells with N-and C-terminal propeptides still attached on each side of the molecule. Subsequent cleavage of the propeptides by specialized Nand C-proteinases triggers self-assembly of the mature collagen into fibrils. The fibrils co-assemble with a variety of different extracellular matrix molecules into the structural scaffold of skin, bone, and other connective tissues. Most mutations disrupting the structure of the type I collagen triple helix (usually substitutions of one of the obligatory Gly residues) cause moderately severe to lethal forms of osteogenesis imperfecta (OI), 2 which is a clinically heterogeneous group of disorders characterized by bone fragility and skeletal deformity (1-3).In our previous study (4) we described a distinct group of ␣1(I)-OI/ EDS patients with combined clinical symptoms of the type III or IV OI as well as laxity of large and small joints and paraspinal ligaments more characteristic of Ehlers-Danlos syndrome (EDS). All of them had structural mutations within the first 90 N-terminal residues of the helical region of the ␣1(I) chain (five Gly substitutions and a 15-aa deletion). Their mutations altered procollagen structure within the N-propeptide cleavage site, resulting in incorporation of pN-collagen with uncleaved N-propeptid...

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“…Other type I collagen-rich tissues, such as the skin, are rarely affected. 26,37 OI has been documented previously in cattle, sheep, domestic cats, mice, and tigers. 1,2,10,11,14,16,18,19,21,23,31 In dogs, OI has been reported in Golden Retrievers, Collies, Poodles, Beagles, Norwegian Elkhound, and Bedlington Terriers.…”

Section: Introductionmentioning

confidence: 99%

Osteogenesis Imperfecta in Two Litters of Dachshunds

Seeliger¹,

Leeb²,

Peters³

et al. 2003

Vet Pathol

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Abstract.A clinical, morphologic, ultrastructural, and genetic study was performed on five rough-coated dachshund semisiblings with osteogenesis imperfecta (OI). Clinical signs consisted of pain, spontaneous bone and teeth fractures, joint hyperlaxity, and reduced bone density on radiography. Primary teeth were extremely thin-walled and brittle. The hallmark of the disease was a severe osteopenia characterized by impairment of lamellar bone formation in the long bones, skull, and vertebral column. No deformity or dwarfism was present. The columns of chondrocytes and primary trabeculae in the epiphyses and metaphyses were histologically normal. An abrupt failure of secondary spongiosa and lamellar bone formation was evident in the medullary and cortical zones in all animals. The few existing trabeculae consisted of woven bone. There was no increase in the number and size of osteoclasts or lacunae. In the teeth, the dentine layers were thin and lacked a tubular pattern. Ultrastructurally, osteoid apposition on bone surfaces was reduced, and small numbers of large cytoplasmic vacuoles were present in a few osteoblasts. Molecular analyses of the collagen type I-encoding genes COL1A1 and COL1A2 revealed several nucleotide differences compared with the published canine sequences but were not significant for OI. Therefore, OI in these Dachshund litters was characterized by a severe, generalized osteopenia and dentinopenia. This pattern of reduced bone formation is suggestive of defective production of collagen type I.

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Partial COL1A2 gene duplication produces features of osteogenesis imperfecta and Ehlers-Danlos syndrome type VII

Cited by 36 publications

References 28 publications

A large tandem duplication within the COL4A5 gene is responsible for the high prevalence of Alport syndrome in French Polynesia

A large tandem duplication within the COL4A5 gene is responsible for the high prevalence of Alport syndrome in French Polynesia

Molecular Mechanism of α1(I)-Osteogenesis Imperfecta/Ehlers-Danlos Syndrome

Osteogenesis Imperfecta in Two Litters of Dachshunds

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