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At least 19 recordsLinked to original sources

PubMed2002

Analysis of the COL3A1 gene in patients with spontaneous cervical artery dissections.

The etiology of spontaneous cervical artery dissection (sCAD) is unknown. An underlying connective tissue disorder has been suggested. As a collagen disease is conceivable several genes encoding fibrillar collagens have been condsidered as candidate genes for sCAD. We analysed the COL3A1 gene in patients with spontaneous cervical artery dissection (sCAD) and in healthy controls, using three different genetic methods. 1) The promoter region, the 5' and 3' untranscribed regions and the N- and C- peptide encoding regions were studied by direct sequencing analysis of DNA from 12 patients. 2) A possible association of sCAD and the COL3A1 gene was tested for with 5 different DNA polymorphisms in 45 patients and 50 healthy control subjects. 3) DNA samples from a father and his two daughters, all suffering from spontaneous dissections of a cervical artery, were analysed with CA-repeat markers that flank the COL3A1 locus. No disease-causing mutations were found in an extended sequence analysis of the COL3A1 gene in patients with sCAD. However, we identified a single nucleotid polymorphism (SNP) in the promotor region in 2 patients and a 2 bp deletion in the 3' UTR in 7 patients. These sequence variants were also found among 50 healthy subjects. An analysis of multiple DNA polymorphisms of the COL3A1 locus in patients and healthy control persons did not indicate a significant association of sCAD with COL3A1. A deletion polymorphism in the 3' UTR was, however, found more often amongst patients with sCAD. The possible linkage of a hypothetical disease mutation with the COL3A1 locus was tested in a small family with three affected patients. As the affected daughters did not inherit the same COL3A1 allele from their affected father (LOD < - 2.3) COL3A1 was excluded as a disease gene in this family. This study confirms and extends earlier work which suggests that COL3A1 mutations are not a major cause for isolated sCAD.

Adult↗

PubMed2004

Association between COL3A1 collagen gene exon 31 polymorphism and risk of floppy mitral valve/mitral valve prolapse.

BACKGROUND: Collagen structure is a key element in mitral valves. Collagen defects were proposed as the primary events causing floppy mitral valves (FMV). The role of collagen genetic variant in floppy mitral valve/mitral valve prolapse (FMV/MVP) has not been well studied. The purpose of this study is to investigate the possible relationship between the collagen gene polymorphisms and risk of FMV/MVP among the Chinese population in Taiwan. METHODS: We studied 100 patients with FMV/MVP diagnosed by echocardiography and 243 age- and sex-matched normal control subjects. The polymorphisms of exon 31 and exon 52 of the collagen type III-alpha1 gene (COL3A1) were identified by polymerase chain reaction (PCR)-based restriction analysis. RESULTS: There was a significant difference in either the genotype distribution (P<0.0001) or allelic frequencies (P<0.0001) between FMV/MVP cases and controls for COL3A1 exon 31 polymorphism. An odds ratio for risk of FMV/MVP associated with COL3A1 exon 31 GG genotype was 7.42 (95% confidence interval 4.40-12.52). An odds ratio for risk of FMV/MVP associated with COL3A1 exon 31 G allele was 2.28 (95% confidence interval 1.57-3.29). There was no significant difference in the distribution of COL3A1 exon 52 genotypes (P=0.31) and allelic frequencies (P=0.32) between FMV/MVP cases and controls. Further categorization of the FMV/MVP patients into mild and severe subgroups revealed no statistical difference from the controls for exon 31 or exon 52 polymorphism. CONCLUSIONS: This study shows that patients with FMV/MVP have higher frequency of COL3A1 exon 31 GG genotype that supports a role of the COL3A1 exon 31 polymorphism in determining the risk of FMV/MVP among the Chinese population in Taiwan.

Adolescent↗

PubMed2002

Genetic variability in the extracellular matrix as a determinant of cardiovascular risk: association of type III collagen COL3A1 polymorphisms with coronary artery disease.

Although common genetic variants in platelet collagen receptors influence platelet activation and thrombosis, the impact of polymorphisms in collagen genes on cardiovascular disease is unknown. To evaluate this, we genotyped a highly polymorphic intronic tandem repeat of the COL3A1 gene, encoding collagen type III, alpha 1. This revealed 4 common alleles (COL3A1-1, -2, -3, and -4). The 2 populations studied were as follows: (1) a cross-sectional study of 703 acute coronary syndrome (ACS) patients with myocardial infarction (MI) and unstable angina, and (2) a prospective study of 924 Caucasian patients from the OPUS (Orbofiban in Patients with Unstable coronary Syndromes)-TIMI-16 trial of the oral GPIIb/IIIa antagonist orbofiban. In addition, we studied 306 control subjects and 224 patients with stable angina. In the case-control population, COL3A1-4 carriers were protected against ACS (odds ratio [OR] = 0.57, 95% CI = 0.35-0.91, P =.02) and stable angina (OR = 0.35, 95% CI = 0.16-0.74, P =.006). In the OPUS population, allele 4 again appeared protective against composite end points (death, MI, stroke, recurrent ischemia, and urgent rehospitalization) (relative risk [RR] = 0.41, 95% CI = 0.17-1.00). There were significant interactions between COL3A1-1 and -3 variants and treatment. Allele COL3A1-3 was associated with an increased risk of the composite end point (RR = 1.65, 95% CI = 1.07-2.55) in patients randomized to orbofiban, but appeared protective in placebo patients (RR = 0.53, 95% CI = 0.28-0.98). We conclude that variants in the COL3A1 gene, the product of which is a vessel-wall protein and platelet ligand, modulate the risk of coronary artery disease and could also modulate the response to antithrombotic therapy. This is the first reported association between polymorphisms of extracellular matrix components and cardiovascular risk.

Alanine↗

PubMed1994

Linkage mapping of the gene for type III collagen (COL3A1) to human chromosome 2q using a VNTR polymorphism.

The gene for the alpha 1 (III) chain of type III collagen, COL3A1, has been previously mapped to human chromosome 2q24.3-q31 by in situ hybridization. Physical mapping by pulsed-field gel electrophoresis has demonstrated that COL3A1 lies within 35 kb of COL5A2. We genotyped the CEPH families at the COL3A1 locus using a pentanucleotide repeat polymorphism within intron 25. We demonstrated significant linkage to 18 anonymous markers as well as the gene for carbamyl phosphate synthetase (CPSI), which we have previously mapped to this region. No recombination was seen between COL3A1 and COL5A2 (Z = 9.93 at theta = 0) or D2S24 (Z = 10.55 at theta = 0). The locus order is (D2S32-D2S138-D2S148)--(D2S24-COL5A2-CO L3A1)--(D2S118-D2S161), with odds of 1:2300 for the next most likely order. These relationships are consistent with the physical mapping of COL3A1 to the distal portion of 2q and place it proximal to CPSI by means of multipoint analysis. These linkage relationships should prove useful in further studies of Ehlers-Danlos syndrome type IV and carbamyl phosphate synthetase I deficiency and provide an additional framework for localizing other genes in this region.

Base Sequence↗

PubMed1993

Parental somatic and germ-line mosaicism for a multiexon deletion with unusual endpoints in a type III collagen (COL3A1) allele produces Ehlers-Danlos syndrome type IV in the heterozygous offspring.

Ehlers-Danlos syndrome (EDS) type IV is a dominantly inherited disorder that results from mutations in the type III collagen gene (COL3A1). We studied the structure of the COL3A1 gene of an individual with EDS type IV and that of her phenotypically normal parents. The proband was heterozygous for a 2-kb deletion in COL3A1, while her father was mosaic for the same deletion in somatic and germ cells. In fibroblasts from the father, approximately two-fifths of the COL3A1 alleles carried the deletion, but only 10% of the COL3A1 alleles in white blood cells were of the mutant species. The deletion in the mutant allele extended from intron 7 into intron 11. There was a 12-bp direct repeat in intron 7 and intron 11, the latter about 60 bp 5' to the junction. At the breakpoint there was a duplication of 10 bp from intron 11 separated by an insertion of 4 bp contained within the duplicated sequence. The father was mosaic for the deletion so that the gene rearrangement occurred during his early embryonic development prior to lineage allocation. These findings suggest that at least some of the deletions seen in human genes may occur during replication, rather than as a consequence of meiotic crossing-over, and that they thus have a risk for recurrence when observed de novo.

Adult↗

PubMed1990

Mapping of Col3a1 and Col6a3 to proximal murine chromosome 1 identifies conserved linkage of structural protein genes between murine chromosome 1 and human chromosome 2q.

We have investigated the degree of synteny between the long arm (q) of human chromosome 2 and the proximal portion of mouse chromosome 1. To define the limits of synteny, we have determined whether mouse homologs of seven human genes mapping to chromosome 2q cosegregated with anchor loci on mouse chromosome 1. The loci investigated were NEB/Neb, ELN/Eln, COL3A1/Col3a1, CRYG/Len-2, FN1/Fn-1, VIL/Vil, and COL6A3/Col6a3. Ren-1,2 and Acrg were included as two proximal mouse chromosome 1 anchor loci. The segregation of restriction fragment length polymorphisms at these loci was analyzed in the progeny of Mus spretus x C57BL/6J hybrids backcrossed to the C57BL/6J inbred strain. We found that five of the structural protein loci and the two anchor loci form a linkage group on proximal murine chromosome 1. The proposed gene order of this group of linked markers is centromere - Col3a1 - Len-2-Fn-1-Vil-Acrg-Col6a3-Ren1,2. Neb and Eln are linked neither to each other nor to any other marker on proximal mouse chromosome 1. Therefore, the mouse loci Col3a1 and Col6a3 are identified as flanking markers of the linkage group of structural protein loci. The estimated genetic map distances are Col3a1-13.3 cM-Len-2-3.4 cM-Fn-1-3.8 cM-Vil-9.6 cM-Acrg-2.1 cM-Col6a3-18.3 cM-Ren1,2. The available map information for human chromosome 2q markers and mouse chromosome 1 markers presented here tentatively identifies Col3a1 and Col6a3 as the border markers that define the limits of the syntenic chromosome segment. The order of mouse genes on chromosome 1 and their human homologs on chromosome 2q also appears to be conserved, suggesting that mapping of murine genes on the conserved segment may be useful to predict gene order in man.

Animals↗

PubMed2001

Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV.

Mutations in the COL3A1 gene that encodes the chains of type III procollagen result in the vascular form of Ehlers-Danlos syndrome (EDS), EDS type IV, if they alter the sequence in the triple-helical domain. Although other fibrillar collagen-gene mutations that lead to allele instability or failure to incorporate proalpha-chains into trimers-and that thus reduce the amount of mature molecules produced-result in clinically apparent phenotypes, no such mutations have been identified in COL3A1. Furthermore, mice heterozygous for Col3a1 "null" alleles have no identified phenotype. We have now found three frameshift mutations (1832delAA, 413delC, and 555delT) that lead to premature termination codons (PTCs) in exons 27, 6, and 9, respectively, and to allele-product instability. The mRNA from each mutant allele was transcribed efficiently but rapidly degraded, presumably by the mechanisms of nonsense-mediated decay. In a fourth patient, we identified a point mutation, in the final exon, that resulted in a PTC (4294C-->T [Arg1432Ter]). In this last instance, the mRNA was stable but led to synthesis of a truncated protein that was not incorporated into mature type III procollagen molecules. In all probands, the presenting feature was vascular aneurysm or rupture. Thus, in contrast to mutations in genes that encode the dominant protein of a tissue (e.g., COL1A1 and COL2A1), in which "null" mutations result in phenotypes milder than those caused by mutations that alter protein sequence, the phenotypes produced by these mutations in COL3A1 overlap with those of the vascular form of EDS. This suggests that the major effect of many of these dominant mutations in the "minor" collagen genes may be expressed through protein deficiency rather than through incorporation of structurally altered molecules into fibrils.

Alleles↗

PubMed1986

Ehlers-Danlos syndrome type IV: cosegregation of the phenotype to a COL3A1 allele of type III procollagen.

Ehlers-Danlos syndrome (EDS) type IV is a rare and catastrophic genetic disorder of the connective tissue. Individuals from two families with this disorder were studied for a restriction fragment length polymorphism (RFLP) associated with the COL3A1 gene. Our results suggested cosegregation of the EDS type IV phenotype with a COL3A1 RFLP allele. Biochemical studies in cultured skin fibroblasts indicated the presence of different mutations affecting the stability and secretion of the pro alpha 1(III) chains of type III procollagen in the two families, thus suggesting that EDS type IV is biochemically heterogeneous. Our data demonstrated the feasibility of molecular diagnosis in this condition using COL3A1 gene related RFLPs.

Alleles↗

PubMed1996

A dimorphic Alu Sb-like insertion in COL3A1 is ethnic-specific.

Alu elements are a class of repetitive DNA sequences found throughout the human genome that are thought to be duplicated via an RNA intermediate in a process termed retroposition. Recently inserted Alu elements are closely related, suggesting that they are derived from a single source gene or closely related source genes. Analysis of the type III collagen gene (COL3A1) revealed a polymorphic Alu insertion in intron 8 of the gene. The Alu insertion in the COL3A1 gene had a high degree of nucleotide identity to the Sb family of Alu elements, a family of older Alu elements. The Alu sequence was less similar to the consensus sequence for the PV or Sb2 subfamilies, subfamilies of recently inserted Alu elements. These data support the observations that at least three source genes are active in the human genome, one of which is distinct from the PV and Sb2 subfamilies and predates either of these two subfamilies. Appearance of the Alu insertion in different ethnic populations suggests that the insertion may have occurred in the last 100,000 years. This Alu insert should be a useful marker for population studies and for marking COL3A1 alleles.

Alleles↗

PubMed1989

Cloning and analysis of the 5' portion of the human type-III procollagen gene (COL3A1).

We have isolated overlapping clones containing the 5'-terminal portion of the human pro-alpha 1(III) collagen gene (COL3A1). This has enabled us to extend our previous studies and thus generate a restriction map of nearly 64 kb of DNA encompassing all of COL3A1 and more than 20 kb of flanking sequences. Aside from the complete nucleotide and amino acid sequences of type-III N-pre-propeptide, this study has established the number of the corresponding exons, whose relative organization deviates from the pattern observed in the analogous regions of type-I procollagen genes, COL1A1 and COL1A2. Moreover, we have sequenced 1628 bp of the 5'-flanking region of COL3A1, from the transcription start point (tsp) to an AluI repetitive element. Pairwise comparison with the analogous segment of the mouse gene has showed 78% sequence similarity in nearly 270 bp immediately preceding the tsp and including the TATA element and a presumptive NF-1 binding site. Relatively close to the tsp, but upstream from the region of homology with the murine gene, a potential AP-1 binding site has also been identified.

Amino Acid Sequence↗

PubMed1992

A 15 base-pair AT-rich variable number tandem repeat in the type III procollagen gene (COL3A1) as an informative marker for 2q31-2q32.3.

Segments of repeating DNA, termed variable number tandem repeats, within the genome are often used as polymorphic markers. Here we report such a repeat in the intervening sequence 25 of the type III procollagen gene (COL3A1) located at 2q31-q32.3. The region containing intervening sequence 25 of the COL3A1 gene was amplified using the polymerase chain reaction and the products were analyzed by agarose gel electrophoresis and dideoxynucleotide sequencing. The repeat consisted of an AT-rich unit of 15 base-pairs (ATATATATATGAGAC). Seven different alleles were identified containing between three and nine repeats of the 15 base-pair unit. The allele heterozygosity was 73% in 117 unrelated individuals. The alleles were shown to be inherited in a Mendelian fashion in three large families. This marker should prove useful in linkage studies for COL3A1, and for linkage studies of other genes on the long arm of chromosome 2. The information extends and complements a report on the same repeat recently published by Lee et al. (J. Biol. Chem. 266: 5256, 1991 a).

Alleles↗

PubMed2001

Genomic organization of the human COL3A1 and COL5A2 genes: COL5A2 has evolved differently than the other minor fibrillar collagen genes.

We report here on the complete structure of the human COL3A1 and COL5A2 genes. Collagens III and V, together with collagens I, II and XI make up the group of fibrillar collagens, all of which share a similar structure and function; however, despite the similar size of the major triple-helical domain, the number of exons coding for the domain differs between the genes for the major fibrillar collagens characterized so far (I, II, and III) and the minor ones (V and XI). The main triple-helical domain being encoded by 49-50 exons, including the junction exons, in the COL5A1, COL11A1 and COL11A2 genes, but by 43-44 exons in the genes for the major fibrillar collagens. Characterization of the genomic structure of the COL3A1 gene confirmed its association with the major fibrillar collagen genes, but surprisingly, the genomic organization of the COL5A2 gene was found to be similar to that of the COL3A1 gene. We also confirmed that the two genes are located in tail-to-tail orientation with an intergenic distance of approximately 22 kb. Phylogenetic analysis suggested that they have evolved from a common ancestor gene. Analysis of the genomic sequences identified a novel single nucleotide polymorphism and a novel dinucleotide repeat. These polymorphisms should be useful for linkage analysis of the Ehlers-Danlos syndrome and related disorders.

Animals↗

PubMed1997

Mutations in the COL3A1 gene result in the Ehlers-Danlos syndrome type IV and alterations in the size and distribution of the major collagen fibrils of the dermis.

Ehlers-Danlos syndrome type IV (EDS type IV) results from heterozygosity for mutations in the COL3A1 gene that encodes the chains of type III procollagen. By using light, transmission, and scanning electron microscopy, we examined skin biopsies from 22 individuals with EDS type IV in whom the COL3A1 mutations had been identified. The most striking changes in EDS type IV were correlated with point mutations that substituted a residue for a glycine near the carboxyl-terminal end of the triple-helical domain of pro alpha1(III). In three cases with the mutation G1012R, G1018V, or G1021E, cells in the dermis had extremely dilated rough endoplasmic reticulum (RER), the dermis was thin, and there was a reduced proportion of collagen although the proportion of elastic fibers appeared increased. In these tissues, collagen fibrils were small (65-80 nm) compared to normal (95-110 nm). Fibrils 80-90 nm in diameter and moderately dilated RER were found with mutations G769R, G373R, and G061E and with exon-skipping mutations of exons 34 and 45. With mutations G034R and G016C and exon-skipping mutations that deleted the sequences of exons 7, 8, 14, 18, 24, and 27, fibrils were more variable in size (85-120 nm). The composite collagen fibrils characteristic of EDS types I and II were not found in EDS type IV. These findings indicate that mutations in the COL3A1 gene have effects on secretion, fibrillogenesis, and skin architecture that reflect the position and nature of the mutation.

Adult↗

PubMed2000

Characterization of 11 new mutations in COL3A1 of individuals with Ehlers-Danlos syndrome type IV: preliminary comparison of RNase cleavage, EMC and DHPLC assays.

We report on 12 patients with EDS IV in whom clinical diagnosis was confirmed by biochemical analysis of collagen type III, and further proven by mutation analysis of the COL3A1 gene. Four overlapping RT-PCR products covering the coding sequence for the triple-helical domain of type III collagen were analyzed by direct sequencing. So far, we have identified, 4 base changes at donor splice junctions, and 1 base change at an acceptor splice site, which all affect mRNA splicing; 1 genomic deletion, which removes exon 45; and 6 nucleotide changes, which cause substitutions of glycine residues within the triple helix. Eleven of the 12 identified mutations are newly recognized. Furthermore, we report a preliminary comparison of RNase cleavage, EMC and DHPLC assays in mutation detection in the COL3A1 gene.

Adolescent↗

PubMed1991

Exclusion of COL1A1, COL1A2, and COL3A1 genes as candidate genes for Ehlers-Danlos syndrome type I in one large family.

Ehlers-Danlos syndrome (EDS) type I is a generalized connective tissue disorder, the major manifestations of which are soft, velvety hyperextensible skin and moderately severe joint hypermobility. The gene defect or defects causing EDS type I have not yet been defined, but previous observations suggested that the syndrome may be caused by mutations in the genes for type-I collagen (COL1A1 and COL1A2) or type-III collagen (COL3A1). Here, we performed linkage studies for these three genes in large Azerbaijanian family with EDS type I. Three polymorphisms in the COL3A1 gene, two in the COL1A1 gene, and one in the COL1A2 gene were tested using the polymerase chain reaction. The data obtained excluded linkage of any of the three genes to EDS type I in the family.

Base Sequence↗

PubMed1988

Genetic distance of two fibrillar collagen loci, COL3A1 and COL5A2, located on the long arm of human chromosome 2.

Two of the human fibrillar collagen genes, proa1(III) (COL3A1) and proa2(V) (COL5A2), map to the same region of the long arm of chromosome 2. To establish the genetic distance between the two loci, we analyzed the segregation of COL3A1 and COL5A2 RFLPs in five families informative for the two loci specific markers. We found that the maximum lod score was 9.33 at a recombination frequency of theta = 0.00. The data therefore provide strong evidence for tight linkage between two evolutionarily related fibrillar collagen genes on the 2q14----2q32 segment of chromosome 2.

Amino Acid Sequence↗

PubMed1990

Physical mapping by PFGE localizes the COL3A1 and COL5A2 genes to a 35-kb region on human chromosome 2.

The genes encoding the alpha 1 chain of Type III collagen (COL3A1) and the alpha 2 chain of Type V (COL5A2) collagen have been mapped to the long arm of human chromosome 2. Linkage analysis in CEPH families indicated that these two genes are close to each other, with no recombination in 37 informative meioses. In the present study, DNA probes from the 3' ends of each gene have been physically mapped by pulsed-field gel electrophoresis. The probes recognized 11 macrorestriction fragments in common, ranging from greater than 1000 kb MluI and NotI fragments to a 35-kb SfiI fragment. Therefore, the COL3A1 and COL5A2 genes appear to exist as a gene cluster on chromosome 2. This is the third example of a collagen gene cluster. Other examples include the COL4A1-COL4A2 genes on chromosome 13q and the COL6A1-COL6A2 genes on chromosome 21q. The physical proximity of these genes may indicate common evolution and/or regulation.

Chromosome Mapping↗

PubMed2005

Multiple proteins are involved in the protein-DNA complex in the proximal promoter of the human alpha1(III) collagen gene (COL3A1).

We have characterized the proximal promoter of the human alpha1(III) collagen gene (COL3A1). Transient transfection assays using a series of chimeric constructs linked to the luciferase gene indicated that the segment from -96 to -34 is necessary to activate transcription. Electrophoretic mobility shift assays (EMSAs) showed that the multiple proteins form the DNA-protein complex in different combinations depending on the cell types. A competition assay using mutant oligonucleotides showed that the sequence 5'-GCTCTCATATTTCAGAA-3' (-79 to -63 bp) is critical for DNA-protein complex formation. This sequence is contained in the B element of mouse alpha1(III) collagen gene (Col3a1) reported by Ruteshouse and de Crombrugghe (J. Biol. Chem., 1993). In the rhabdomyosarcoma cell line, A204, at least two proteins of 92-118 kDa and 40-52 kDa are involved in the DNA-protein complex bound to this motif.

Animals↗