Arg<sup>519</sup>‐Cys Mutation in COL2A1: Evidence for Multiple Foundersa

Bleasel, J. F.; Holderaum, D.; Brancolini, Valeria; Moskowitz, R. W.; Haqqi, Tariq M.; Considine, Eileen L.; Prockop, Darwin J.; Devoto, Marcella; Williams, Charlene J.

doi:10.1111/j.1749-6632.1996.tb56265.x

Cited by 12 publications

(7 citation statements)

References 2 publications

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“…The question arose as to whether the families with the Arg 519 3 Cys mutation represented multiple occurrences of this mutation, or whether all families were derived from a common founder. Linkage disequili brium analysis of COL2A1 polymorphisms associated with the Arg 519 3 Cys mutation showed that of 4 families tested, the 2 families from Michigan and New Zealand were probably descended from the same founder, based on the finding that these 2 families share association with a relatively rare allele of COL2A1 (31). Further analysis in our laboratory demonstrated that the same mutation associated with this rare allele was present in the Icelandic family as well.…”

mentioning

confidence: 66%

Genetics and osteoarthritis: Exposing the iceberg

Holderbaum

Haqqi

Moskowitz

1999

Arthritis & Rheumatism

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confidence: 66%

Genetics and osteoarthritis: Exposing the iceberg

Holderbaum

Haqqi

Moskowitz

1999

Arthritis & Rheumatism

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“…The importance of correct conformation of the triple-helical region for the proper structure and function of skeletal tissues is clearly evidenced by a number of aberrations of these tissues caused by mutations in COL2A1 ( OMIM# 120140 ). In particular, single amino acid substitutions in collagen II are responsible for a broad spectrum of chondrodysplasia phenotypes, generally described as spondyloepiphyseal dysplasia (SED), whose main feature is abnormalities of skeletal development1,7,8,9,10,11,12,13. The most frequent amino acid substitutions in collagen II occur at the “G” position of the G-X-Y triplets but substitutions in the “Y” positions were also described.…”

Section: Introductionmentioning

confidence: 99%

R992C (p.R1192C) Substitution in Collagen II Alters the Structure of Mutant Molecules and Induces the Unfolded Protein Response

Chung

Jensen

Gawron

et al. 2009

Journal of Molecular Biology

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SummaryWe investigated the molecular bases of spondyloepiphyseal dysplasia (SED) associated with the R992C (p.R1192C) substitution in collagen II. At the protein level we analyzed the structure and integrity of mutant molecules, and at the cellular level we specifically studied the effects of the presence of the R992C collagen II on the biological processes taking place in host cells. Our studies demonstrated that mutant collagen II molecules were characterized by altered electrophoretic mobility, relatively low thermostability, the presence of atypical disulfide bonds, and slow rates of secretion into the extracellular space. Analyses of cellular responses to the presence of the mutant molecules showed that excessive accumulation of thermolabile collagen II was associated with the activation of an "unfolded protein response" and an increase in apoptosis of host cells. Collectively, these data suggest that molecular mechanisms of SED may be driven not only by structural changes in the architecture of extracellular collagenous matrices, but also by intracellular processes activated by the presence of mutant collagen II molecules.

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“…The presence of skeletal defects in patients harboring mutations in COL2A1 (MIM] 120140) underlines the importance of a proper structure of type II collagen for the development and the integrity of skeletal tissues [Bleasel et al, 1995[Bleasel et al, , 1996a[Bleasel et al, , 1996bKnowlton et al, 1990;Kuivaniemi et al, 1991;Olsen, 1995;Prockop and Kivirikko, 1995].…”

Section: Introductionmentioning

confidence: 99%

Cells expressing partially unfolded R789C/p.R989C type II procollagen mutant associated with spondyloepiphyseal dysplasia undergo apoptosis

et al. 2008

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We investigated the effects of the presence of R75C (p.R275C), R519C (p.719C), R789C (p.R989C), and G853E (p.G1053E) type II collagen (COL2A1) mutants, associated with distinct forms of spondyloepiphyseal dysplasia (SED), on the biological processes occurring in chondrocytic cells harboring those mutants. Mutant-specific biological responses of cells were initiated by activating tetracycline (Tet)-dependent expression of type II collagen mutants. Employing microscopic and biochemical assays, we determined that cells expressing the thermolabile R789C (p.R989C) type II collagen mutant undergo apoptosis. In contrast, in cells expressing the thermostable R75C (p.R275C), R519C (p.719C), and G853E (p.G1053E) mutants, apoptotic markers were not apparent. We also demonstrated that the R789C (p.R989C) mutant formed atypical complexes with endoplasmic reticulum (ER)-resident chaperones, thereby indicating an "unfolded protein response" (UPR) of cells harboring this specific mutant. Apoptotic changes were also demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and cleaved caspase 3 assays in the growth plates of mice harboring the R992C (p.R1147C) substitution in type II collagen. Based on these results, we propose that the intracellular presence of structurally altered type II collagen mutants could activate an apoptotic response, thereby limiting cell survival. By analyzing the response of cells to the altered structure of collagen mutants, our study contributes to better understanding the molecular basis of the pathological changes seen in vivo at the tissue level.

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Arg⁵¹⁹‐Cys Mutation in COL2A1: Evidence for Multiple Foundersa

Cited by 12 publications

References 2 publications

Genetics and osteoarthritis: Exposing the iceberg

Genetics and osteoarthritis: Exposing the iceberg

R992C (p.R1192C) Substitution in Collagen II Alters the Structure of Mutant Molecules and Induces the Unfolded Protein Response

Cells expressing partially unfolded R789C/p.R989C type II procollagen mutant associated with spondyloepiphyseal dysplasia undergo apoptosis

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Arg519‐Cys Mutation in COL2A1: Evidence for Multiple Foundersa

Cited by 12 publications

References 2 publications

Genetics and osteoarthritis: Exposing the iceberg

Genetics and osteoarthritis: Exposing the iceberg

R992C (p.R1192C) Substitution in Collagen II Alters the Structure of Mutant Molecules and Induces the Unfolded Protein Response

Cells expressing partially unfolded R789C/p.R989C type II procollagen mutant associated with spondyloepiphyseal dysplasia undergo apoptosis

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Arg⁵¹⁹‐Cys Mutation in COL2A1: Evidence for Multiple Foundersa