An osteopenic nonfracture syndrome with features of mild osteogenesis imperfecta associated with the substitution of a cysteine for glycine at triple helix position 43 in the pro alpha 1(I) chain of type I collagen.

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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Substitutions of aspartic acid for glycine-220 and of arginine for glycine-664 in the triple helix of the pro α1(I) chain of type I procollagen produce lethal osteogenesis imperfecta and disrupt the ability of collagen fibrils to incorporate crystalline hydroxyapatite

Biochemical Journal ◽

10.1042/bj3110815 ◽

1995 ◽

Vol 311 (3) ◽

pp. 815-820 ◽

Cited By ~ 16

Author(s):

A A Culbert ◽

M P Lowe ◽

M Atkinson ◽

P H Byers ◽

G A Wallis ◽

...

Keyword(s):

Osteogenesis Imperfecta ◽

Aspartic Acid ◽

Triple Helix ◽

Type I Collagen ◽

Collagen Fibrils ◽

Morphological Data ◽

Type I ◽

Type Ii ◽

Col1a1 Gene ◽

Type I Procollagen

We identified two infants with lethal (type II) osteogenesis imperfecta (OI) who were heterozygous for mutations in the COL1A1 gene that resulted in substitutions of aspartic acid for glycine at position 220 and arginine for glycine at position 664 in the product of one COL1A1 allele in each individual. In normal age- and site-matched bone, approximately 70% (by number) of the collagen fibrils were encrusted with plate-like crystallites of hydroxyapatite. In contrast, approximately 5% (by number) of the collagen fibrils in the probands' bone contained crystallites. In contrast with normal bone, the c-axes of hydroxyapatite crystallites were sometimes poorly aligned with the long axis of fibrils obtained from OI bone. Chemical analysis showed that the OI samples contained normal amounts of calcium. The probands' bone samples contained type I collagen, overmodified type I collagen and elevated levels of type III and V collagens. On the basis of biochemical and morphological data, the fibrils in the OI samples were co-polymers of normal and mutant collagen. The results are consistent with a model of fibril mineralization in which the presence of abnormal type I collagen prevents normal collagen in the same fibril from incorporating hydroxyapatite crystallites.

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Abnormal type I collagen glycosylation pattern and cross-linking in a cyclophilin B KO mouse model of recessive osteogenesis imperfecta

Bone Abstracts ◽

10.1530/boneabs.1.pp501 ◽

2013 ◽

Author(s):

Wayne Cabral ◽

Irina Perdivara ◽

MaryAnn Weis ◽

Masahiko Terajima ◽

Angela Blissett ◽

...

Keyword(s):

Mouse Model ◽

Osteogenesis Imperfecta ◽

Type I Collagen ◽

Cross Linking ◽

Type I ◽

Glycosylation Pattern ◽

Cyclophilin B

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Restoration of Osteogenesis by CRISPR/Cas9 Genome Editing of the Mutated COL1A1 Gene in Osteogenesis Imperfecta

Journal of Clinical Medicine ◽

10.3390/jcm10143141 ◽

2021 ◽

Vol 10 (14) ◽

pp. 3141

Author(s):

Hyerin Jung ◽

Yeri Alice Rim ◽

Narae Park ◽

Yoojun Nam ◽

Ji Hyeon Ju

Keyword(s):

Osteogenesis Imperfecta ◽

Type I Collagen ◽

Disease Modeling ◽

Bone Fragility ◽

Osteogenic Potential ◽

Type I ◽

Gene Correction ◽

Col1a1 Gene ◽

Collagen Formation

Osteogenesis imperfecta (OI) is a genetic disease characterized by bone fragility and repeated fractures. The bone fragility associated with OI is caused by a defect in collagen formation due to mutation of COL1A1 or COL1A2. Current strategies for treating OI are not curative. In this study, we generated induced pluripotent stem cells (iPSCs) from OI patient-derived blood cells harboring a mutation in the COL1A1 gene. Osteoblast (OB) differentiated from OI-iPSCs showed abnormally decreased levels of type I collagen and osteogenic differentiation ability. Gene correction of the COL1A1 gene using CRISPR/Cas9 recovered the decreased type I collagen expression in OBs differentiated from OI-iPSCs. The osteogenic potential of OI-iPSCs was also recovered by the gene correction. This study suggests a new possibility of treatment and in vitro disease modeling using patient-derived iPSCs and gene editing with CRISPR/Cas9.

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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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