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

Chung, Hye Jin; Jensen, Deborah; Gawron, Katarzyna; Steplewski, Andrzej; Fertala, Andrzej

doi:10.1016/j.jmb.2009.05.004

Cited by 31 publications

(67 citation statements)

References 42 publications

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“…The unfolded protein stress response (UPR) has been implicated in OA progression. We and others have reported that collagen mutant mouse strains Dmm, Cho and Sedc exhibit distended ER and Golgi, consistent with the mis-folded type II collagen being trapped in the ER rather than secreted to the extracellular matrix [15,16]. We have previously reported a 1.66 fold increase in BiP expression in Dmm/+ newborn articular cartilage compared to wild type (p = 0.01).…”

supporting

confidence: 74%

Collagen Mutant Mouse Models Provide an Important Tool to Study Osteoarthritis

Rose¹,

Seegmiller²,

Bridgewater³

et al. 2016

J Arthritis

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Mutations in the human type II (COL2A1) collagen gene appear to be the basis for many skeletal disorders such as spondyloepiphyseal dysplasia [1], achondrogenesis, Kniest, and Stickler syndrome [2]. Several of these conditions include early-onset osteoarthritis in addition to the chondrodysplasia phenotype [3]. Other collagen genes are also involved etiologically in the chondrodysplasias, e.g., an autosomal dominant form of Stickler syndrome, characterized by mild spondyloepiphyseal dysplasia (SED) and early-onset osteoarthritis, results from a mutation involving the COL11A2 gene that encodes the α2 (XI) chain of the quantitatively minor fibrillar type XI collagen [4]. Multiple epiphyseal dysplasia in humans involving flattening of the epiphyses, shortening of endochondral bones, and early-onset osteoarthritis has been linked to a mutation in type IX collagen [5], and mice made transgenic for α1 (IX) mutation have been shown to develop osteoarthritis and intervertebral disc degeneration prematurely [6]. The Disproportionate micromelia (Dmm) mouse has a mutation that causes lethal dwarfism in the homozygote and mild dwarfism in the heterozygote. This strain of mouse has a threenucleotide deletion in the C-propeptide region of the Col2a1 gene, a gene highly conserved with its human homologue, COL2A1 [7]. Both genes encode for type II collagen, the most abundant protein in hyaline cartilage [8]. As a result of the Col2a1 deletion, Dmm/+ mice have a decrease of proteoglycan production in the hyaline cartilage that typically yields early onset degradation and OA. We have previously reported OA-like changes in a mouse model that bears a mutation in the Col2a1 gene, similar to that found in humans, that behaves as a recessive mutation resulting in no obvious phenotype in the heterozygote [9]. The mouse mutation was named spondyloepiphesial dysplasia congenita (sedc) [10] because when homozygous it produces features that resemble the most common clinical phenotypes of SED congenita in humans [11]. Thus in both mouse and human it is known that collagen gene mutations that lead to a wide variety of disorders of the skeletal system can also lead to premature osteoarthritis.While chondrodysplasia models of OA have been important in advancing our understanding of OA, the majority of OA cases in humans are not associated with any recognizable features of chondrodysplasia. This raises the question of whether the cartilage collagen genes play a significant role in the majority of human OA, or are only relevant in the minority of cases associated with chondrodysplasias. It has been shown that, in fact, at least two different heterozygous point mutations in the triple helical domain of the COL2A1 gene can cause degenerative joint disease in humans in the absence of other phenotypic abnormalities [12]. We have also shown that the heterozygous sedc mouse, although morphometrically normal, exhibits early onset OA [9]. This puzzle was solved, in part, when we demonstrated using electron microscopy that compared with controls, mutant ...

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supporting

confidence: 74%

Collagen Mutant Mouse Models Provide an Important Tool to Study Osteoarthritis

Rose¹,

Seegmiller²,

Bridgewater³

et al. 2016

J Arthritis

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“…, Fabry’s and Gaucher’s diseases (Yam et al 2006; Maor et al 2013; Ron et al 2010); and in the pathology of diseases involving professional secretory tissues such as cystic fibrosis and α1-antitrypsin deficiency (Bartoszewski et al 2011; Alam et al 2014). Recent reports investigating effects of mutations on assembly and secretion of several ECM components suggest that multiple outcomes such as misfolding and intracellular accumulation of mutant ECM proteins may result from induction of ER stress (Chung et al 2009; Liang et al 2014; Rajpar et al 2009; Pieri et al 2014; Firtina et al 2009; Gould et al 2007; Nugent et al 2009; Bateman et al 2009; Boot-Handford and Briggs 2010; Yang et al 2005). …”

Section: Endoplasmic Reticulum Stress and The Diseasesmentioning

confidence: 99%

“…Although individually rare, they cause a significant impact on the quality of life for patients suffering from skeletal abnormalities. Genes encoding cartilage ECM proteins affected by mutations which disrupt growth plate differentiation comprise collagen types II, IX, X, and XI; aggrecan; cartilage oligomeric matrix protein (COMP); and matrilin 3 (Hintze et al 2008; Chung et al 2009; Liang et al 2014; Ho et al 2007; Mäkitie et al 2010; Kuivaniemi et al 1997; Warman et al 2011; Bateman et al 2009; Boot-Handford and Briggs 2010; Yang et al 2005; Briggs et al 2015). The list of collagenopathies associated with mutations in collagen types II and X is presented in Table 1.…”

Section: Mutations Leading To Cartilage Pathologymentioning

confidence: 99%

“…These modifications include hydroxylation of proline residues and lysine residues by prolyl-4 hydroxylase (P4H) and lysyl hydroxylase (LH), respectively. In turn, the posttranslational modifications and formation of the triple-helical structure are controlled by molecular chaperones that belong to the group of proteins residing in the ER, which includes heat shock protein 47 (HSP47), Grp78, and protein disulfide isomerase (PDI), amongst which the latter enzyme also acts as the β subunit of the αα/ββ tetramer that constitutes functional P4H (Chung et al 2009; Ono et al 2012; Patterson and Dealy 2014). In addition, by binding to the individual pro-α1(II) chains and preventing their premature association, P4H may also act as a chaperone during biosynthesis of procollagen molecules.…”

Section: Mutations In Collagen Type IImentioning

confidence: 99%

“…In recent years, accumulating evidence indicates that abnormal folding and accumulation of structural proteins that are produced to fulfil their physiological function in the extracellular space of tissues may lead to ER stress and induction of a wide range of systemic diseases. For instance, several reports linked ER stress to mutations in collagen type II that induce various forms of spondyloepiphyseal dysplasia (SED) (Chung et al 2009; Okada et al 2015; Liang et al 2014). Other studies highlight the role of ER stress in the pathogenesis of metaphyseal (chondro) dysplasia, Schmid type (MCDS), a disorder caused by mutations in the collagen type X, characterized by expansion of the hypertrophic zone of the growth plate resulting in dwarfism (Rajpar et al 2009; Ho et al 2007; Mäkitie et al 2010).…”

Section: Introductionmentioning

confidence: 99%

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Endoplasmic reticulum stress in chondrodysplasias caused by mutations in collagen types II and X

Gawron

2016

Cell Stress and Chaperones

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The endoplasmic reticulum is primarily recognized as the site of synthesis and folding of secreted, membrane-bound, and some organelle-targeted proteins. An imbalance between the load of unfolded proteins and the processing capacity in endoplasmic reticulum leads to the accumulation of unfolded or misfolded proteins and endoplasmic reticulum stress, which is a hallmark of a number of storage diseases, including neurodegenerative diseases, a number of metabolic diseases, and cancer. Moreover, its contribution as a novel mechanistic paradigm in genetic skeletal diseases associated with abnormalities of the growth plates and dwarfism is considered. In this review, I discuss the mechanistic significance of endoplasmic reticulum stress, abnormal folding, and intracellular retention of mutant collagen types II and X in certain variants of skeletal chondrodysplasia.

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Genetic Disorders of the Extracellular Matrix

Lamandé

Bateman

2019

The Anatomical Record

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Mutations in the genes for extracellular matrix (ECM) components cause a wide range of genetic connective tissues disorders throughout the body. The elucidation of mutations and their correlation with pathology has been instrumental in understanding the roles of many ECM components. The pathological consequences of ECM protein mutations depend on its tissue distribution, tissue function, and on the nature of the mutation. The prevalent paradigm for the molecular pathology has been that there are two global mechanisms. First, mutations that reduce the production of ECM proteins impair matrix integrity largely due to quantitative ECM defects. Second, mutations altering protein structure may reduce protein secretion but also introduce dominant negative effects in ECM formation, structure and/or stability. Recent studies show that endoplasmic reticulum (ER) stress, caused by mutant misfolded ECM proteins, makes a significant contribution to the pathophysiology. This suggests that targeting ER-stress may offer a new therapeutic strategy in a range of ECM disorders caused by protein misfolding mutations. Anat Rec,

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

Cited by 31 publications

References 42 publications

Collagen Mutant Mouse Models Provide an Important Tool to Study Osteoarthritis

Collagen Mutant Mouse Models Provide an Important Tool to Study Osteoarthritis

Endoplasmic reticulum stress in chondrodysplasias caused by mutations in collagen types II and X

Genetic Disorders of the Extracellular Matrix

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