Severe (type III) osteogenesis imperfecta due to glycine substitutions in the central domain of the collagen triple helix

Type I collagen alpha 1(I) glycine to serine substitutions, resulting from G-to-A mutations, were defined in three cases of osteogenesis imperfecta (OI). The Gly substitutions displayed a gradient of phenotypic severity according to the location of the mutation in the collagen triple helix. The most C-terminal of these, Gly565 to Ser, led to the lethal perinatal (type II) form of OI, whereas the more N-terminal mutations, Gly415 and Gly352 to Ser, led to severe OI (type III/IV) and moderate OI (type IVB) respectively. These data support the notion that glycine substitutions towards the C-terminus of the alpha 1(I) or alpha 2(I) chains will be more clinically severe than those towards the N-terminus. This results from the more disruptive effect of the mutations at the C-terminus on helix initiation and C- and N-terminal helix directional propagation. This generalization must be modified by considering the nature of the glycine substitution and the surrounding amino acid sequence, since the helix is composed of subdomains of differing stability which will affect the ability of helix re-nucleation and propagation.

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Changes in collagen stability and folding in lethal perinatal osteogenesis imperfecta. The effect of α1(I)-chain glycine-to-arginine substitutions

Biochemical Journal ◽

10.1042/bj2610253 ◽

1989 ◽

Vol 261 (1) ◽

pp. 253-257 ◽

Cited By ~ 14

Author(s):

A T Baker ◽

J A M Ramshaw ◽

D Chan ◽

W G Cole ◽

J F Bateman

Keyword(s):

Osteogenesis Imperfecta ◽

Molecular Modelling ◽

Triple Helix ◽

Structural Abnormality ◽

Denaturation Temperature ◽

Collagen Triple Helix ◽

Helix Formation ◽

Helix Structure ◽

Collagen Stability

The effect of glycine-to-arginine mutations in the alpha 1 (I)-chain on collagen triple-helix structure in lethal perinatal osteogenesis imperfecta was studied by determination of the helix denaturation temperature and by computerized molecular modelling. Arginine substitutions at glycine residues 391 and 667 resulted in similar small decreases in helix stability. Molecular modelling suggested that the glycine-to-arginine-391 mutant resulted in only a relatively small localized disruption to the helix structure. Thus the glycine-to-arginine substitutions may lead to only a small structural abnormality of the collagen helix, and it is most likely that the over-modification of lysine, poor secretion, increased degradation and other functional sequelae result from a kinetic defect in collagen helix formation resulting from the mutation.

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NANOINDENTATION MEASUREMENT ON INTERSTITIAL AND OSTEON OF BONE WITH OSTEOGENESIS IMPERFECTA-TYPE III

Journal of Mechanical Engineering Research and Developments ◽

10.26480/jmerd.04.2019.168.171 ◽

2019 ◽

Vol 42 (4) ◽

pp. 168-171

Author(s):

N. A. Azizan ◽

K. S. Basaruddin ◽

M. H. Mat Som ◽

S. F. Khan ◽

A. R. Sulaiman ◽

...

Keyword(s):

Osteogenesis Imperfecta ◽

Osteogenesis Imperfecta Type ◽

Type Iii ◽

Nanoindentation Measurement

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Faculty Opinions recommendation of Crystal structure of the collagen triple helix model [(Pro-Pro-Gly)(10)](3).

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1004876.56455 ◽

2002 ◽

Author(s):

Patricia C Weber

Keyword(s):

Crystal Structure ◽

Triple Helix ◽

Collagen Triple Helix ◽

Triple Helix Model

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The Role of Collagen Triple Helix Repeat-Containing 1 Protein (CTHRC1) in Rheumatoid Arthritis

International Journal of Molecular Sciences ◽

10.3390/ijms22052426 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2426

Author(s):

Askhat Myngbay ◽

Limara Manarbek ◽

Steve Ludbrook ◽

Jeannette Kunz

Keyword(s):

Rheumatoid Arthritis ◽

Drug Targets ◽

Triple Helix ◽

Cancer Metastasis ◽

Bone Erosion ◽

Cartilage Destruction ◽

Patient Treatment ◽

Collagen Triple Helix ◽

Potential Biomarker

Rheumatoid arthritis (RA) is a chronic autoimmune disease causing inflammation of joints, cartilage destruction and bone erosion. Biomarkers and new drug targets are actively sought and progressed to improve available options for patient treatment. The Collagen Triple Helix Repeat Containing 1 protein (CTHRC1) may have an important role as a biomarker for rheumatoid arthritis, as CTHRC1 protein concentration is significantly elevated in the peripheral blood of rheumatoid arthritis patients compared to osteoarthritis (OA) patients and healthy individuals. CTHRC1 is a secreted glycoprotein that promotes cell migration and has been implicated in arterial tissue-repair processes. Furthermore, high CTHRC1 expression is observed in many types of cancer and is associated with cancer metastasis to the bone and poor patient prognosis. However, the function of CTHRC1 in RA is still largely undefined. The aim of this review is to summarize recent findings on the role of CTHRC1 as a potential biomarker and pathogenic driver of RA progression. We will discuss emerging evidence linking CTHRC1 to the pathogenic behavior of fibroblast-like synoviocytes and to cartilage and bone erosion through modulation of the balance between bone resorption and repair.

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Intracellular and Extracellular Markers of Lethality in Osteogenesis Imperfecta: A Quantitative Proteomic Approach

International Journal of Molecular Sciences ◽

10.3390/ijms22010429 ◽

2021 ◽

Vol 22 (1) ◽

pp. 429

Author(s):

Luca Bini ◽

Domitille Schvartz ◽

Chiara Carnemolla ◽

Roberta Besio ◽

Nadia Garibaldi ◽

...

Keyword(s):

Osteogenesis Imperfecta ◽

Type I Collagen ◽

Type I ◽

Tandem Mass ◽

Type Ii ◽

Type Iii ◽

Bioinformatic Tools ◽

Proteomic Approach ◽

Fibrillin 1 ◽

Heritable Disorder

Osteogenesis imperfecta (OI) is a heritable disorder that mainly affects the skeleton. The inheritance is mostly autosomal dominant and associated to mutations in one of the two genes, COL1A1 and COL1A2, encoding for the type I collagen α chains. According to more than 1500 described mutation sites and to outcome spanning from very mild cases to perinatal-lethality, OI is characterized by a wide genotype/phenotype heterogeneity. In order to identify common affected molecular-pathways and disease biomarkers in OI probands with different mutations and lethal or surviving phenotypes, primary fibroblasts from dominant OI patients, carrying COL1A1 or COL1A2 defects, were investigated by applying a Tandem Mass Tag labeling-Liquid Chromatography-Tandem Mass Spectrometry (TMT LC-MS/MS) proteomics approach and bioinformatic tools for comparative protein-abundance profiling. While no difference in α1 or α2 abundance was detected among lethal (type II) and not-lethal (type III) OI patients, 17 proteins, with key effects on matrix structure and organization, cell signaling, and cell and tissue development and differentiation, were significantly different between type II and type III OI patients. Among them, some non–collagenous extracellular matrix (ECM) proteins (e.g., decorin and fibrillin-1) and proteins modulating cytoskeleton (e.g., nestin and palladin) directly correlate to the severity of the disease. Their defective presence may define proband-failure in balancing aberrances related to mutant collagen.

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Modulating the collagen triple helix formation by switching: Positioning effects of depsi-defects on the assembly of [Gly-Pro-Pro]7 collagen mimetic peptides

European Polymer Journal ◽

10.1016/j.eurpolymj.2018.12.045 ◽

2019 ◽

Vol 112 ◽

pp. 301-305 ◽

Cited By ~ 3

Author(s):

Matthias Röber ◽

Sophie Laroque ◽

Sandra A. Lopez ◽

Thomas Scheibel ◽

Hans G. Börner

Keyword(s):

Triple Helix ◽

Collagen Triple Helix ◽

Helix Formation ◽

Mimetic Peptides ◽

Triple Helix Formation ◽

Collagen Mimetic Peptides

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Type I Collagen Biosynthesis by Skin Fibroblasts from Patients with Idiopathic Juvenile Osteoporosis

Clinical Science ◽

10.1042/cs0890069 ◽

1995 ◽

Vol 89 (1) ◽

pp. 69-73 ◽

Cited By ~ 7

Author(s):

Andrew E. Pocock ◽

Martin J. O. Francis ◽

Roger Smith

Keyword(s):

Osteogenesis Imperfecta ◽

Type I Collagen ◽

The Other ◽

Type I ◽

Osteogenesis Imperfecta Type ◽

Unrelated Control ◽

Type Iii ◽

Collagen Peptides ◽

Idiopathic Juvenile Osteoporosis ◽

Osteogenesis Imperfecta Type I

1. Skin fibroblast lines were cultured from nine patients who had the features of idiopathic juvenile osteoporosis, six relatives, five unrelated control subjects and three unrelated patients with osteogenesis imperfecta type I. Some patients with idiopathic juvenile osteoporosis were adults whose previous osteoporosis was in remission. Two patients with idiopathic juvenile osteoporosis were siblings and one patient with idiopathic juvenile osteoporosis had a daughter with severe osteogenesis imperfecta (type III). 2. The ratio of type III to type I collagen, synthesized by fibroblasts, was increased in two of the patients with osteogenesis imperfecta type I and in the daughter with osteogenesis imperfecta type III, but was normal in all the other patients with idiopathic juvenile osteoporosis and the other relatives. 3. Radiolabelled collagen was digested by cyanogen bromide and separated on SDS-PAGE. Unreduced collagen peptides migrated normally, except those from both the two siblings with idiopathic juvenile osteoporosis. In these two lines, abnormal migration suggested the presence of collagen I mutations. 4. The secretion of synthesized collagen by these two idiopathic juvenile osteoporosis lines and two others was reduced to only 43–45% as compared with a line from a 13-year-old control subject, which was defined as 100%. The three osteogenesis imperfecta type I lines secreted 18–37%, the other five idiopathic juvenile osteoporosis lines secreted 57–75%, the relatives (including the daughter with severe osteogenesis imperfecta) secreted 49–115% and the controls secreted 69–102%. 5. We conclude that qualitative abnormalities of type I collagen associated with a reduction in total secreted collagen synthesis may occur in a minority of patients with idiopathic juvenile osteoporosis; these patients could represent a subset of patients with this disorder.

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