Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia.

Ala‐Kokko, Leena; Baldwin, Clinton T.; Moskowitz, Roland W.; Prockop, Darwin J.

doi:10.1073/pnas.87.17.6565

Cited by 238 publications

(132 citation statements)

References 26 publications

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“…Glycine codons are present in the first position of the Gly-X-Y triplet, which is a basic repeated motif of the triple helix. Arginine replacements with cysteine (Arg75Cys, Arg519Cys, Arg789Cys) in the Y-position of the triplets were originally found in patients with SED and early onset osteoarthritis, early onset osteoarthritis with mild chondrodysplasia, and a severe form of SEDC [Ala-Kokko et al, 1990;Chan et al, 1993;Williams et al, 1993]. However, no other Y-position substitutions have been reported.…”

Section: Introductionmentioning

confidence: 99%

Novel amino acid substitution in the Y‐position of collagen type II causes spondyloepimetaphyseal dysplasia congenita

Sułko

Czarny-Ratajczak

Woźniak

et al. 2005

American J of Med Genetics Pt A

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We report on monozygotic twins with short stature and severe spondyloepimetaphyseal dysplasia congenita (SEMDC) from the Polish population. Phenotype of the twin girls resembles spondyloepiphyseal dysplasia congenita Spranger-Wiedemann (SEDC-SW), but shortening of the stature is more severe and the cranioface is normal. The distinctive radiographic features, in spite of similarity to SEDC-SW, indicate different spinal and, notably, severe metaphyseal involvement. Molecular analysis of the COL2A1 gene revealed an A to G transition at nucleotide þ79 of exon 41 that converted the codon for arginine at amino acid 792 to a codon for glycine (Arg792Gly). The twins were heterozygous for the mutation and neither parent had this change. The Arg792Gly substitution is located at the Y-position of Gly-X-Y triplet, and it is likely that this substitution decreased the thermal stability of the triple helix and may affect fibril growth by replacement of an arginine residue, which is important for a conformation of the triple helix.

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Section: Introductionmentioning

confidence: 99%

Novel amino acid substitution in the Y‐position of collagen type II causes spondyloepimetaphyseal dysplasia congenita

Sułko

Czarny-Ratajczak

Woźniak

et al. 2005

American J of Med Genetics Pt A

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“…Type II collagen is considered as a critical phenotypic marker gene for analysis of molecular events involved in chondrogenesis process as well as in chondrocyte phenotype maintenance. Alteration of type II collagen expression in cartilage may be due to a variety of genetic, inflammatory, or degenerative circumstances and may lead to a variety of chondrodysplasias and joint diseases such as osteoarthritis (3)(4)(5)(6)(7)(8). In osteoarthritis, chondrocytes undergo dedifferentiation and synthesize types I and III collagens at the expense of type II (9 -11).…”

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confidence: 99%

SP3 Represses the SP1-mediated Transactivation of the HumanCOL2A1 Gene in Primary and De-differentiated Chondrocytes

Ghayor¹,

Chadjichristos²,

Herrouin³

et al. 2001

Journal of Biological Chemistry

127

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Sp1 and Sp3 effects on the transcription of the human ␣1(II) procollagen gene (COL2A1) were investigated in both differentiated and de-differentiated rabbit articular chondrocytes. Transient transfection with constructs of deleted COL2A1 promoter sequences driving the luciferase reporter gene revealed that the region spanning ؊266 to ؉121 base pairs showed Sp1-enhancing effects, whatever the differentiation state. In contrast, Sp3 did not influence COL2A1 gene transcription. Concomitant overexpression of the two Sp proteins demonstrated that Sp3 blocked the Sp1 induction of COL2A1 promoter activity. Moreover, inhibition of Sp1/ Sp3 binding to their target DNA sequence decreased both COL2A1 gene transcription and Sp1-enhancing effects. DNase I footprinting and gel retardation assays revealed that Sp1 and Sp3 bind specifically to cis-sequences of the COL2A1 gene promoter whereby they exert their transcriptional effects. Sp1 and Sp3 levels were found to be reduced in de-differentiated chondrocytes, as revealed by DNA-binding and immunochemical study. Sp1 specifically activated collagen neosynthesis whatever the differentiation state of chondrocytes, suggesting that this factor exerts a major role in the expression of collagen type II. However, our data indicate that type II collagen-specific expression in chondrocytes depend on both the Sp1/Sp3 ratio and cooperation of Sp1 with other transcription factors, the amounts of which are also modulated by phenotype alteration.Differentiation of mesenchymal cells into chondrocytes results in the synthesis and secretion of a series of proteins characteristic of the cartilage matrix, including type II, IX, XI, and X collagens, the proteoglycan aggrecan, link protein, and cartilage matrix protein (1, 2). Type II collagen is considered as a critical phenotypic marker gene for analysis of molecular events involved in chondrogenesis process as well as in chondrocyte phenotype maintenance. Alteration of type II collagen expression in cartilage may be due to a variety of genetic, inflammatory, or degenerative circumstances and may lead to a variety of chondrodysplasias and joint diseases such as osteoarthritis (3-8). In osteoarthritis, chondrocytes undergo dedifferentiation and synthesize types I and III collagens at the expense of type II (9 -11). Similarly, when chondrocytes are subcultured in vitro as monolayers, they progressively reduce their synthesis of type II collagen (12-14), mimicking the behavior of osteoarthritic chondrocytes. However, they can recover the chondrocytic phenotype by transfer to three-dimensional culture systems (14 -16). Therefore, in vitro analysis of the molecular mechanisms that regulate COL2A1 gene expression can be an approach to understand the process of phenotype alteration in chondrocytes, and its impact on joint diseases.A 48-bp 1 minimal DNA element has been identified as an enhancer that directs chondrocyte-specific expression of the COL2A1 gene in transgenic mice (17)(18)(19). Such an element was also found in the rat COL2A1 gene (20, 21). ...

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“…p.(Arg550Cys), c.1648C4T was novel, but p.(Arg719Cys), c.2155C4T has already been reported once in a patient with osteoarthritis and mild chondrodysplasia. 10 Eyre et al 11 have demonstrated that p.(Arg719Cys), c.2155C4T is responsible for a reduction in protein secretion and a limited collagen assembly. The fourth arginine to cystein variant, p.(Arg904Cys), c.2710C4T, was found once in a Stickler case and once in a Kniest case, from our series.…”

Section: Discussionmentioning

confidence: 99%

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

Barat‐Houari

Dumont²,

Fabre³

et al. 2015

Eur J Hum Genet

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Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.

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Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia.

Cited by 238 publications

References 26 publications

Novel amino acid substitution in the Y‐position of collagen type II causes spondyloepimetaphyseal dysplasia congenita

Novel amino acid substitution in the Y‐position of collagen type II causes spondyloepimetaphyseal dysplasia congenita

SP3 Represses the SP1-mediated Transactivation of the HumanCOL2A1 Gene in Primary and De-differentiated Chondrocytes

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

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