Disease relevance of COL2A1

• This mutation emphasizes the importance of COL2A1 mutations in producing the spondyloepiphyseal dysplasia phenotype [1].
• The data obtained exclude linkage of Marfan syndrome to the two major fibrillar collagen (COL1A1, COL1A2, and COL2A1) genes [2].
• A novel mutation of COL2A1 resulting in dominantly inherited rhegmatogenous retinal detachment [3].
• Mutations at two loci, COL2A1 and FGFR3, account for most patients with chondrodysplasias--those with spondyloepiphyseal dysplasia and the achondroplasia classes of disorders, respectively [4].
• Boy with syndactylies, macrocephaly, and severe skeletal dysplasia: not a new syndrome, but two dominant mutations (GLI3 E543X and COL2A1 G973R) in the same individual [5].

Psychiatry related information on COL2A1

• Gender, type, and size of housing, insulation standard of housing, daycare, exposure to passive cigarette smoking, and dietary habits were not associated with AOM, rAOM, or COM in the surveyed children [6].

High impact information on COL2A1

• These results demonstrate that COL2A1 expression is directly regulated by SOX9 protein in vivo and implicate abnormal regulation of COL2A1 during, chondrogenesis as a cause of the skeletal abnormalities associated with campomelic dysplasia [7].
• Furthermore, ectopic expression of Sox9 trans-activates both a COL2A1-driven reporter gene and the endogenous Col2a1 gene in transgenic mice [7].
• Our data support the hypothesis that some cases, if not all cases, of this distinctive chondrodysplasia result from dominant mutations in COL2A1, thus expanding the clinical spectrum of phenotypes associated with this gene [8].
• Genetic linkage of a polymorphism in the type II procollagen gene (COL2A1) to primary osteoarthritis associated with mild chondrodysplasia [9].
• These cell lines also expressed reporter gene constructs containing regulatory sequences (-577/+3,428 bp) of the type II collagen gene (COL2A1) in transient transfection experiments, and IL-1 beta suppressed this expression by 50-80% [10].

Chemical compound and disease context of COL2A1

• Mutation in type II procollagen (COL2A1) that substitutes aspartate for glycine alpha 1-67 and that causes cataracts and retinal detachment: evidence for molecular heterogeneity in the Wagner syndrome and the Stickler syndrome (arthro-ophthalmopathy) [11].
• A single base mutation in the type II procollagen gene (COL2A1) that converts glycine alpha 1-247 to serine in a family with late-onset spondyloepiphyseal dysplasia [12].
• OBJECTIVE: An arginine-to-cysteine substitution at position 519 of the COL2A1 gene causes early generalized osteoarthritis with mild chondrodysplasia in humans [13].
• OBJECTIVE: To test for the reexpression of the chondroprogenitor splice variant of the gene COL2A1, type IIA procollagen (containing a cysteine-rich NH2 propeptide), in adult articular chondrocytes in osteoarthritic (OA) joint disease [14].
• Mutation in the COL2A1 gene has been identified in one family with spondyloepiphyseal dysplasia and calcium pyrophosphate and apatite crystalline deposits [15].

Biological context of COL2A1

• Mutation of these sequences abolishes SOX9 binding and chondrocyte-specific expression of a COL2A1-driven reporter gene (COL2A1-lacZ) in transgenic mice [7].
• These data extend the mutation spectrum of the COL2A1 gene and help explain the basis for the different vitreous phenotypes seen in Stickler syndrome [16].
• The two genes of type I collagen, COL1A1 and COL2A1, have been mapped previously to chromosomes 17 and 7, respectively [17].
• In a large family with linkage to COL2A1, with a LOD score of 2.8, a unique L467F mutation produced a novel "afibrillar" vitreous gel devoid of all normal lamella structure [16].
• It has an autosomal dominant inheritance pattern and is caused by mutations in COL2A1, COL11A1, and COL11A2 [18].

Anatomical context of COL2A1

• Restriction endonuclease analysis of DNA from human-rodent hybrid cell lines in conjunction with in situ hybridization of human metaphasic chromosomes have shown that the gene coding for the pro alpha 1 chain of type II collagen (COL2A1) is located on chromosome 12 in the segment 12q131----12q132 [19].
• Cultured dermal fibroblasts were shown, using amplification of cDNA by the polymerase chain reaction, to produce very low levels of spliced transcripts from the COL2A1 gene that encodes the cartilage-specific alpha 1(II) chains of type II collagen [1].
• In this study, it was confirmed that the mRNA expression of ra-a47 and COL2A1, a type II collagen gene, was upregulated on stimulation with transforming growth factor (TGF) beta in chondrocytes [20].
• METHODS: Clinical examination of the family and linkage analysis using markers flanking COL2A1 and COL11A1, the known loci for Stickler syndrome; mutation screening of COL2A1; construction of splicing reporter minigenes and transfection into cultured cells; and RT-PCR analysis of reporter specific transcripts [3].
• Transcription of the type-II procollagen gene (COL2A1) is very specifically restricted to a limited number of tissues, particularly cartilages [21].

Associations of COL2A1 with chemical compounds

• The p38 MAPK-selective inhibitor, SB203580, partially reversed IL-1beta-induced inhibition of COL2A1 mRNA levels and COL2A1-luciferase reporter gene expression [22].
• However, in contrast, inflammatory cytokines such as tumor necrosis factor (TNF) alpha, interferon (IFN) beta, and interleukin (IL)-6 downregulated the expression of ra-a47 mRNA, whereas the expression of COL2A1 mRNA was not repressed, or even upregulated, in HCS-2/8 cells [20].
• Several mutations causing Stickler syndrome have been found in the COL2A1 gene, and one mutation causing Stickler syndrome and one causing Marshall syndrome have been detected in the COL11A1 gene [23].
• DNA sequencing showed a transition of C2913T in exon 41 of one allele of the COL2A1 gene resulting in the substitution of arginine 789 by cysteine in the alpha 1 (II) chain [24].
• Linkage to the collagen COL2A1 locus was demonstrated and a cytosine to adenosine transition identified within exon 2, leading to the creation of a stop codon at position 86 (Cys86Stop) [25].

Physical interactions of COL2A1

• Nevertheless, IL-1 beta decreased the binding activity of both Sp1 and Sp3 to the 63-bp short COL2A1 promoter, suggesting that the cytokine exerts a post-transcriptional regulatory mechanism on Sp1 and Sp3 gene expressions [26].

Regulatory relationships of COL2A1

• Transfection of decoy Sp-binding oligonucleotides corroborated the implication of the proximal promoter in the TGF-beta1-induced inhibition of COL2A1 gene transcription [27].
• These studies also show, for the first time, that p38 MAPK is one of the signals required for IL-1beta-induced inhibition of COL2A1 gene expression [22].
• IL-1 beta down-regulates COL2A1 gene transcription through a -41/-33 bp sequence that binds a multimeric complex including Sp1 and Sp3 transcription factors [26].
• A 1.9-Kb 5' fragment from the human COL1A1 gene drives inappropriate expression of the human COL2A1 gene in tissues of transgenic mice that normally express only the COL1A1 gene [28].

Other interactions of COL2A1

• These findings suggest that TGF-beta1 inhibition of COL2A1 gene transcription in RAC is mediated by an increase of the Sp3/Sp1 ratio and by the repression of Sp1 transactivating effects on that gene [27].
• We identified highly conserved sequence elements upstream of the AAUAAA in three human collagen genes, COL1A1, COL1A2, and COL2A1, and demonstrate that these upstream sequence elements (USEs) influence polyadenylation efficiency [29].
• Similarly, COL2A1 expression in P9 cells increased fivefold compared to P4 cells, while COL10A1 levels remained unchanged [30].
• These results suggest that SOX9 is not the key regulator of COL2A1 promoter activity in human adult articular chondrocytes [31].
• The COMP gene mutation (C348R), while not previously published, is typical of those in PSACH patients, whereas the COL2A1 mutation (T1370M) is somewhat atypical, as it predicts an amino acid change within the carboxyl-terminal region of the protein [32].

Analytical, diagnostic and therapeutic context of COL2A1

• The COL2A1 gene was amplified as five overlapping PCR products [33].
• This was confirmed by sequence analysis of amplified COL2A1 cDNA, which revealed a single nucleotide substitution (GGA-->GAA) in 5 of 10 clones [34].
• The same allele shows reduced expression in all three patients, and this allele is more frequent in a well-defined OA population than in a control group, suggesting the possible existence of a rare COL2A1 allele that predisposes to OA [35].
• Sixteen family members underwent a complete physical examination, anthropometric measurements, radiographic studies of the spine and peripheral joints, and analysis of the type II procollagen gene (COL2A1) [36].
• Our findings demonstrate heteroduplex analysis of the COL2A1 VNTR to be a robust and highly informative genetic marker system [37].

References