Papers by Catherine Irven
American Journal of Human Genetics, Jul 1, 1999
We present a two-stage genomewide scan for osteoarthritis-susceptibility loci, using 481 families... more We present a two-stage genomewide scan for osteoarthritis-susceptibility loci, using 481 families that each contain at least one affected sibling pair. The first stage, with 272 microsatellite markers and 297 families, involved a sparse map covering 23 chromosomes at intervals of ∼15 cM. Sixteen markers that showed evidence of linkage at nominal were then taken through P р .05 to the second stage, with an additional 184 families. This second stage confirmed evidence of linkage for markers on chromosome 11q. Additional markers from this region were then typed to create a denser map. We obtained a maximum single-point LOD score, at D11S901, of 2.40 () and a maximum multipoint-LOD P ϭ .0004 score of 3.15, between markers D11S1358 and D11S35. A subset of 196 of the 481 families, comprising affected female sibling pairs, generated a corrected LOD score of 2.54 () for marker D11S901, with evidence P ϭ .0003 for linkage extending 12 cM proximal to this marker. When we stratified for affected male sibling pairs there was no evidence of linkage to chromosome 11. Our data suggest that a female-specific susceptibility gene for idiopathic osteoarthritis is located on chromosome 11q.
Matrix Biology, Sep 1, 1994
Multiple epiphyseal dysplasia (MED) is a dominantly inherited chondrodysplasia characterized by m... more Multiple epiphyseal dysplasia (MED) is a dominantly inherited chondrodysplasia characterized by mild short stature and early-onset osteoarthrosis. Some forms of MED clinically resemble another chondrodysplasia phenotype, the mild form of pseudoachondroplasia (PSACH). On the basis of their clinical similarities as well as similar ultrastructural and biochemical features in cartilage from some patients, it has been proposed that MED and PSACH belong to a single bone-dysplasia family. Recently, both mild and severe PSACH as well as a form of MED have been linked to the same interval on chromosome 19, suggesting that they may be allelic disorders. Linkage studies with the chromosome 19 markers were carried out in a large family with MED and excluded the previously identified interval. Using this family, we have identified an MED locus on the short arm of chromosome 1, in a region containing the gene (COL9A2) that encodes the a2 chain of type IX collagen, a structural component of the cartilage extracellular matrix.
Human Genetics, Mar 1, 1994
We have developed a mutation detection strategy that combines single strand conformational polymo... more We have developed a mutation detection strategy that combines single strand conformational polymorphism (SSCP) analysis of one strand of a double-stranded amplification product with direct sequencing of the other. Using this strategy, which we find economical of both time and resources, we have identified a G to A transition, which substitutes a serine for glycine residue at position 862 in the major helix of the ~1 chain of Type I collagen. We use this mutation, which causes a lethal form of osteogenesis imperfecta, to illustrate the technique.
British journal of rheumatology, Apr 1, 2000
Background. In independent linkage studies chromosome 2q11-q24 and chromosome 2q23-35 have previo... more Background. In independent linkage studies chromosome 2q11-q24 and chromosome 2q23-35 have previously been implicated as regions potentially harbouring susceptibility loci for osteoarthritis (OA). Objective. To test chromosome 2q for linkage to idiopathic osteoarthritis. Methods. Using a cohort of 481 OA families that each contained at least one affected sibling pair with severe end-stage disease (ascertained by hip or knee joint replacement surgery), we conducted a linkage analysis of chromosome 2q using 16 polymorphic microsatellite markers at an average spacing of one marker every 8.5 cM. Results. Our results provide suggestive evidence for a locus at 2q31 with a maximum multipoint logarithm of the odds score (MLS) of 1.22 which increased to 2.19 in those families concordant for hip-only disease (n = 311). This suggestive linkage was greater in male-hip families (MLS = 1.57, n = 71) than in female-hip families (MLS = 0.71, n = 132). Conclusions. Chromosome 2q is likely to contain at least one susceptibility locus for OA.
Rheumatology, 2000
Objective. To examine 11 candidate genes as susceptibility loci for osteoarthritis (OA). Methods.... more Objective. To examine 11 candidate genes as susceptibility loci for osteoarthritis (OA). Methods. A total of 481 families have been ascertained in which at least two siblings have had joint replacement surgery of the hip, or knee, or hip and knee for idiopathic OA. Each candidate gene was targeted using one or more intragenic or closely linked microsatellite marker. The linkage data were analysed unstratified and following stratification by sex and by joint replaced (hip or knee). Results. The analyses revealed suggestive linkage of the type IX collagen gene COL9A1 (6q12-q13) to a subset of 132 families that contained affected females who were concordant for hip OA (female-hip) with a P-value of 0.00053 and logarithm of the odds (LOD) score of 2.33 [corrected P-value of 0.0016, corrected LOD score of 1.85]. Conclusions. COL9A1 may therefore be a susceptibility locus for female hip OA. In addition, there was weak evidence of linkage to HLA/COL11A2 (6p21.3) in female hip OA with a corrected P-value of 0.016.
Amer J Hum Genet, 1995
Osteoarthritis (OA) is a common debilitating disease resulting from the degeneration of articular... more Osteoarthritis (OA) is a common debilitating disease resulting from the degeneration of articular cartilage. The major protein of cartilage is type II collagen, which is encoded by the COL2A1 gene. Mutations at this locus have been discovered in several individuals with inherited disorders of cartilage. We have identified 27 primary OA patients who are heterozygous for sequence dimorphisms located in the coding region of COL2A1. These dimorphisms were used to distinguish the mRNA output from each of the two COL2A1 alleles in articular cartilage obtained from each patient. Three patients demonstrated differential allelic expression and produced <12% of the normal level of mRNA from one of their COL2A1 alleles. The same allele shows reduced expression in a well-defined OA population than in a control group, suggesting the possible existence of a rare COL2A1 allele that predisposes to OA. 31 refs., 4 figs., 3 tabs.
American journal of human genetics, 1995
Osteoarthritis (OA) is a common debilitating disease resulting from the degeneration of articular... more Osteoarthritis (OA) is a common debilitating disease resulting from the degeneration of articular cartilage. The major protein of cartilage is type II collagen, which is encoded by the COL2A1 gene. Mutations at this locus have been discovered in several individuals with inherited disorders of cartilage. We have identified 27 primary OA patients who are heterozygous for sequence dimorphisms located in the coding region of COL2A1. These dimorphisms were used to distinguish the mRNA output from each of the two COL2A1 alleles in articular cartilage obtained from each patient. Three patients demonstrated differential allelic expression and produced < 12% of the normal level of mRNA from one of their COL2A1 alleles. 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.
Rheumatology, 2000
Background. In independent linkage studies chromosome 2q11-q24 and chromosome 2q23-35 have previo... more Background. In independent linkage studies chromosome 2q11-q24 and chromosome 2q23-35 have previously been implicated as regions potentially harbouring susceptibility loci for osteoarthritis (OA). Objective. To test chromosome 2q for linkage to idiopathic osteoarthritis. Methods. Using a cohort of 481 OA families that each contained at least one affected sibling pair with severe end-stage disease (ascertained by hip or knee joint replacement surgery), we conducted a linkage analysis of chromosome 2q using 16 polymorphic microsatellite markers at an average spacing of one marker every 8.5 cM. Results. Our results provide suggestive evidence for a locus at 2q31 with a maximum multipoint logarithm of the odds score (MLS) of 1.22 which increased to 2.19 in those families concordant for hip-only disease (n = 311). This suggestive linkage was greater in male-hip families (MLS = 1.57, n = 71) than in female-hip families (MLS = 0.71, n = 132). Conclusions. Chromosome 2q is likely to contain at least one susceptibility locus for OA.
Rheumatology, 1994
Generalized OA (GOA) is a well-characterized subset of primary OA which is strongly associated wi... more Generalized OA (GOA) is a well-characterized subset of primary OA which is strongly associated with the occurrence of Heberden&#39;s nodes. Using gene-specific highly polymorphic markers and affected sib pair (ASP) analyses, we have investigated genetic linkage between GOA and three cartilage matrix genes: COL2A1 which encodes type II collagen; CRTL1 which encodes the cartilage link protein and CRTM which encodes the cartilage matrix protein. The analyses showed no linkage between GOA and the three genes in the 38 sib pairs examined. Since we examined a relatively modest number of sib pairs, our results can only exclude COL2A1, CRTL1 and CRTM as major susceptibility loci for GOA.
Human Mutation, 1998
1. Hum Mutat. 1998;Suppl 1:S10-7. Identification of five novel mutations in cartilage oligomeric ... more 1. Hum Mutat. 1998;Suppl 1:S10-7. Identification of five novel mutations in cartilage oligomeric matrix protein gene in pseudoachondroplasia and multiple epiphyseal dysplasia. Loughlin J, Irven C, Mustafa Z, Briggs MD, Carr ...
Human Molecular Genetics, 1995
Received May 10, 1995; Revised and Accepted June 15, 1995 ... Ehlers-Danlos syndrome (EDS) is a g... more Received May 10, 1995; Revised and Accepted June 15, 1995 ... Ehlers-Danlos syndrome (EDS) is a group of heritable disorders of connective tissue with skin, ligaments and blood vessels being the main sites affected. The commonest variant (EDS II) exhibits an autosomal ...
Human Genetics, 1994
We have developed a mutation detection strategy that combines single strand conformational polymo... more We have developed a mutation detection strategy that combines single strand conformational polymorphism (SSCP) analysis of one strand of a double-stranded amplification product with direct sequencing of the other. Using this strategy, which we find economical of both time and resources, we have identified a G to A transition, which substitutes a serine for glycine residue at position 862 in the major helix of the ~1 chain of Type I collagen. We use this mutation, which causes a lethal form of osteogenesis imperfecta, to illustrate the technique.
Human Genetics, 1994
The chondrodysplasias are characterised by the abnormal development of articulating joints and bo... more The chondrodysplasias are characterised by the abnormal development of articulating joints and bone. Mutations in the COL2A1 and COL10A1 genes, which encode the cartilage collagens type II and type X, have been identified in a variety of inherited chondrodysplasias. However, both genes have also been excluded as the mutant loci in several chondrodysplasia pedigrees, indicating the existence of at least one other chondrodysplasia locus. We report the exclusion of the genes encoding two cartilage-specific proteins, the cartilage link protein and the cartilage matrix protein, in several chondrodysplasia pedigrees in which COL2A1 had previously been excluded as the mutant locus.
The American Journal of Human Genetics, 2000
A randomly ascertained sample of males with the surname "Sykes" was typed with four Y-chromosome ... more A randomly ascertained sample of males with the surname "Sykes" was typed with four Y-chromosome microsatellites. Almost half the sample shared the same Y-chromosome haplotype, which has not been observed in control samples either from the same geographic region or from the United Kingdom as a whole. This points to a single surname founder for extant Sykes males, even though written sources had predicted multiple origins. The distribution of other Sykes Y-chromosome haplotypes were not significantly different from those in controls and may be accounted for by the historical accumulation of nonpaternity during the past 700 years, in which case the average rate estimate is 1.3%/generation. If this pattern is reproduced with other surnames, it may have important forensic and genealogical applications.
The American Journal of Human Genetics, 1999
The American Journal of Human Genetics, 1998
We have used Y-chromosomal polymorphisms to trace paternal lineages in Polynesians by use of samp... more We have used Y-chromosomal polymorphisms to trace paternal lineages in Polynesians by use of samples previously typed for mtDNA variants. A genealogical approach utilizing hierarchical analysis of eight rare-event biallelic polymorphisms, seven microsatellite loci, and internal structural analysis of the hypervariable minisatellite, MSY1, has been used to define three major paternal-lineage clusters in Polynesians. Two of these clusters, both defined by novel MSY1 modular structures and representing 55% of the Polynesians studied, are also found in coastal Papua New Guinea. Reduced Polynesian diversity, relative to that in Melanesians, is illustrated by the presence of several examples of identical MSY1 codes and microsatellite haplotypes within these lineage clusters in Polynesians. The complete lack of Y chromosomes having the M4 base substitution in Polynesians, despite their prevalence (64%) in Melanesians, may also be a result of the multiple bottleneck events during the colonization of this region of the world. The origin of the M4 mutation has been dated by use of two independent methods based on microsatellite-haplotype and minisatellite-code diversity. Because of the wide confidence limits on the mutation rates of these loci, the M4 mutation cannot be conclusively dated relative to the colonization of Polynesia, 3,000 years ago. The other major lineage cluster found in Polynesians, defined by a base substitution at the 92R7 locus, represents 27% of the Polynesians studied and, most probably, originates in Europe. This is the first Y-chromosomal evidence of major European admixture with indigenous Polynesian populations and contrasts sharply with the picture given by mtDNA evidence.
The American Journal of Human Genetics, 1999
We present a two-stage genomewide scan for osteoarthritis-susceptibility loci, using 481 families... more We present a two-stage genomewide scan for osteoarthritis-susceptibility loci, using 481 families that each contain at least one affected sibling pair. The first stage, with 272 microsatellite markers and 297 families, involved a sparse map covering 23 chromosomes at intervals of ∼15 cM. Sixteen markers that showed evidence of linkage at nominal were then taken through P р .05 to the second stage, with an additional 184 families. This second stage confirmed evidence of linkage for markers on chromosome 11q. Additional markers from this region were then typed to create a denser map. We obtained a maximum single-point LOD score, at D11S901, of 2.40 () and a maximum multipoint-LOD P ϭ .0004 score of 3.15, between markers D11S1358 and D11S35. A subset of 196 of the 481 families, comprising affected female sibling pairs, generated a corrected LOD score of 2.54 () for marker D11S901, with evidence P ϭ .0003 for linkage extending 12 cM proximal to this marker. When we stratified for affected male sibling pairs there was no evidence of linkage to chromosome 11. Our data suggest that a female-specific susceptibility gene for idiopathic osteoarthritis is located on chromosome 11q.
Uploads
Papers by Catherine Irven