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Biomedical subjects

K Gardiner

Publications and source records attributed to K Gardiner.

At least 55 records · Page 3Linked to original sources
PubMed1999

Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.

Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukaemia (AML). Informative recombination events in 6 FPD/AML pedigrees with evidence of linkage to markers on chromosome 21q identified an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated with the disease in four FPD/AML pedigrees. We identified heterozygous CBFA2 missense mutations that co-segregated with the disease in the remaining two FPD/AML pedigrees at phylogenetically conserved amino acids R166 and R201, respectively. Analysis of bone marrow or peripheral blood cells from affected FPD/AML individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. Our findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.

Amino Acid Sequence↗
PubMed1999

Comparative genomic analysis of the interferon/interleukin-10 receptor gene cluster.

Interferons and interleukin-10 are involved in key aspects of the host defence mechanisms. Human chromosome 21 harbors the interferon/interleukin-10 receptor gene cluster linked to the GART gene. This cluster includes both components of the interferon alpha/beta-receptor (IFNAR1 and IFNAR2) and the second components of the interferon gamma-receptor (IFNGR2) and of the IL-10 receptor (IL10R2). We report here the complete gene content of this GART-cytokine receptor gene cluster and the use of comparative genomic analysis to identify chicken IFNAR1, IFNAR2, and IL10R2. We show that the large-scale structure of this locus is conserved in human and chicken but not in the pufferfish Fugu rubripes. This establishes that the receptor components of these host defense mechanisms were fixed in an ancestor of the amniotes. The extraordinary diversification of the interferon ligand family during the evolution of birds and mammals has therefore occurred in the context of a fixed receptor structure.

Amino Acid Sequence↗
PubMed1998

Molecular cloning of a human cDNA IGSF3 encoding an immunoglobulin-like membrane protein: expression and mapping to chromosome band 1p13.

We report the isolation and characterization of a novel cDNA IGSF3 that contains a 3648-bp open reading frame encoding an apparent immunoglobulin (Ig)-like membrane protein characterized by eight Ig domains. IGSF3 has an overall structural similarity and strong sequence similarity to V7, a human leukocyte surface protein. The IGSF3 mRNA is highly expressed in placenta, kidney, and lung, but is also present in a wide range of other human tissues. Although a small internal sequence of the IGSF3 cDNA hybridizes to a YAC derived from the centromeric region of chromosome 21, in situ hybridization experiments on human metaphase chromosomes show that the gene corresponding to the long cDNA that we cloned is located in chromosome band 1p13 and that related sequences are located on chromosomes 2 and 13. These data serve to emphasize the potential difficulties in transcriptional mapping in centromeric regions.

Amino Acid Sequence↗
PubMed1998

Analysis of pufferfish homologues of the AT-rich human APP gene.

Mutations in the beta-amyloid precursor protein (APP) gene are associated with some forms of Familial Alzheimer's Disease. The human APP gene is large, the 19 exons span approximately 300 kb, and AT-rich, at 40% GC. We have examined the genomic structure and cDNA sequence of the APP gene in the pufferfish Fugu rubripes and Tetraodon fluviatilis, respectively. In contrast to human, the Fugu APP gene spans less than 10 kb of DNA, with the introns compacted 48-fold on average. Two axons, alternatively processed in humans, are absent in both pufferfish. APP is the largest, most AT-rich gene examined in Fugu and is also the most highly compressed. The genomic sequences spanning the human and the Fugu APP genes were analysed with a set of exon and gene prediction programs. Results show that these are highly reliable for the Fugu gene with lower false positive and false negative rates than are seen in the analysis of the human gene. Comparative analysis of Fugu sequences homologous to very AT-rich regions in the human genome may, therefore, be advantageous in gene-finding efforts, both for their highly reduced sizes and their reliable gene predictions.

Alzheimer Disease↗
PubMed1998

Occupational urothelial tumours: a regional case-control study.

OBJECTIVE: To investigate the role of occupational exposures in the risk of developing urothelial cancer. MATERIALS AND METHODS: Occupational histories, obtained using a self-administered questionnaire, for 803 patients with urothelial cancer (first diagnosed 1991-93) were compared with similar information for 2135 matched controls. Relative risks (RRs) were estimated using conditional logistic regression. Comparisons were also made with historical regional employment information available from the 1971 census. RESULTS: There were many statistically significant positive associations for urothelial cancer risks and ever being employed in specified occupations (with or without statistical adjustment for smoking status in 1991). Smoking-adjusted RRs of > 2.0 were obtained for seven occupations; manufacture of fire lighters/ patent fuels (RR 4.30, 95% confidence interval 0.78-23.79), rodent extermination (3.71, 1.20-11.48), manufacture of dyestuffs (2.61, 0.98-7.00), leather work (2.51, 1.44-4.35), cable manufacturing industry (2.46, 1.20-5.04), textile printing and dyeing (2.32, 0.98-5.45), and sewage works (2.19, 1.16-4.11). Analyses of the occupations followed in 1971 (thus allowing for 20-year latency) indicated an elevated RR for workers in the plastics industry (5.22, 1.57-17.36). CONCLUSIONS: The historical legacy of exposure to aromatic amines in the rubber, cable-making, dyestuffs and other industries remains. An important proportion of patients presenting with urothelial tumours are likely to have had occupational exposure to urothelial carcinogens. A review of occupational exposures in the contemporaneous plastic, textile and leather industries is warranted.

Adult↗
PubMed1998

Risk factors for sensitisation and respiratory symptoms among workers exposed to acid anhydrides: a cohort study.

OBJECTIVES: To examine the relation between exposure to acid anhydrides and the risk of developing immediate skin prick test responses to acid anhydride human serum albumin (AA-HSA) conjugates or work related respiratory symptoms; to assess whether these relations are modified by atopy or smoking. METHODS: A cohort of 506 workers exposed to phthalic (PA), maleic (MA), and trimellitic anhydride (TMA) was defined. Workers completed questionnaires relating to employment history, respiratory symptoms, and smoking habits. Skin prick tests were done with AA-HSA conjugates and common inhalant allergens. Exposure to acid anhydrides was measured at the time of the survey and a retrospective exposure assessment was done. RESULTS: Information was obtained from 401 (79%) workers. Thirty four (8.8%) had new work related respiratory symptoms that occurred for the first time while working with acid anhydrides and 12 (3.2%) were sensitised, with an immediate skin prick test reaction to AA-HSA conjugates. Sensitisation to acid anhydrides was associated with work related respiratory symptoms and with smoking at the time of exposure to acid anhydride. When all subjects were included and all three acid anhydrides were taken into account there was no consistent evidence for an exposure-response relation, but with the analysis restricted to a factory where only TMA was in use there was an increased prevalence of sensitisation to acid anhydrides and work related respiratory symptoms with increasing full shift exposure. This relation was apparent within the current occupational exposure standard of 40 micrograms.m-3 and was not modified significantly by smoking or atopy. CONCLUSIONS: Intensity of exposure and cigarette smoking may be risk factors for sensitisation to acid anhydrides. Exposure is also a risk factor for respiratory symptoms. As there was evidence for sensitisation to TMA at full shift exposures within the occupational exposure standard this standard should be reviewed.

Adolescent↗
PubMed1998

Retrospective exposure assessment for a cohort study into respiratory effects of acid anhydrides.

OBJECTIVES: To estimate past exposure to phthalic (PA), trimellitic (TMA) and maleic anhydride (MA) in three alkyd resin and one cushioned flooring factory to estimate exposure-response relations in a retrospective cohort study. METHODS: Personal exposure measurements were carried out in 1992 and quantitative and qualitative information on past exposure and production processes were collected. Job titles were ranked by decreasing exposure and amalgamated into job categories and exposure groups. Multiplication factors for back calculating past exposure levels were estimated with past exposure data, or if no such data were available these factors were estimated by a panel of occupational hygienists. Exposure levels were back calculated starting with the exposure levels in 1992. RESULTS: High exposures to PA were estimated to have occurred among workers operating the PA melting pots in factory 1 (estimated exposure in 1960-9 was 2480 micrograms.m-3). Highest concentrations of TMA were estimated to have occurred among the ink mixers in factory 2 from 1979 to 1986 (554 micrograms.m-3). Exposure in most other job titles was thought to be fairly constant over time for PA, TMA, and MA. CONCLUSIONS: Exposure to acid anhydride at these factories has fallen during the period covered by the study. However, it is estimated that in only one job in factory 2 did past exposure to acid anhydride exceed the current occupational exposure standard. Accuracy of the estimated exposure is limited by a paucity of reliable past exposure data.

Anhydrides↗
PubMed1997

Clonability and gene distribution on human chromosome 21: reflections of junk DNA content?

Data from transcriptional mapping of human chromosome 21 have been compiled from a number of sources. Regardless of the gene identification technique used, a consistent picture has developed: the centromere proximal half of 21q, which contains 50% of the DNA (20 Mb), harbors only 10% of the expressed sequences. Because of the variety of gene isolation techniques used, this result is unlikely to arise simply from methodological artefacts, biases in clonability or tissue specificity of expression. This region is known to be AT-rich and to contain APP, the largest gene (spanning 300 kb) currently analyzed on 21q. Interesting preliminary data from analysis of the Fugu rubripes homolog of APP has shown an unusually high, 50-fold, compaction of intron size, raising the intriguing possibility that >90% of the DNA in the human gene may be functionless. Thus, data from a variety of approaches suggest that a large part of 21q very likely has neither coding capacity nor associated regulatory function. By these criteria, it is a good candidate for a repository of junk DNA.

Animals↗
PubMed1997

Activation of a novel gene in 3q21 and identification of intergenic fusion transcripts with ecotropic viral insertion site I in leukemia.

We have identified a novel gene, GR6, located within the leukemia breakpoint region of 3q21, that is normally expressed in early fetal development but not in adult peripheral blood. GR6 is activated in the UCSD-AML1 cell line and in a leukemic sample, both of which carry a t(3;3)(q21;q26). In UCSD-AML1, we have also identified fusion transcripts between the ecotropic viral insertion site I (EVI1) gene in 3q26 and GR6 and between EVI1 and Ribophorin I that maps 30 kb telomeric to GR6 in 3q21. All fusions splice the 5' ends of the 3q21 genes into exon 2 of the EVI1 gene, an event that is similar to the normal intergenic splicing of MDS1-EVI1 and to those previously documented in leukemias with t(3;21) and t(3;12), in which acute myelogenous leukemia 1-EVI1 fusions and ETV6-EVI1 fusions, respectively, occur. The Ribophorin I-EVI1 fusion in particular may be a common occurrence in t(3;3).

Adult↗
PubMed1997

Leukemia breakpoint region in 3q21 is gene rich.

Rearrangements of the long arm of human chromosome 3, including reciprocal translocations, inversions and deletion/duplication of bands 3q21-3q26, as well as deletions of 3q21 and reciprocal translocations between 3q21 and other chromosomes, are well documented in leukemia. Previous studies showed that the breakpoints within 3q21 cluster within a 10-40 kb region but no candidate genes were described. In this work, we have identified partial cDNAs corresponding to five to nine new transcripts from an 80 kb P1 clone that spans ten breakpoints. These transcripts, with one exception, appear to be expressed only at low levels in the set of cancer cell lines examined. Four transcripts are located between the previously mapped Ribophorin I gene and the most centromeric breakpoint; three map directly within the 20 kb spanning nine independent breakpoints. These data (i) show that among characterized leukemia breakpoint regions 3q21 is unusually gene rich, (ii) provide new candidates for relevance to leukemia in 3q21, and (iii) suggest possibilities for chromatin configuration effects.

Chromosome Breakage↗
PubMed1997

Map location, genomic organization and expression patterns of the human RED1 RNA editase.

A cDNA fragment containing sequences homologous to the rat RED1 RNA editase gene was recently identified on human chromosome 21. Here we report the location of this cDNA in distal 21q22.3 near the CD18 gene. We also report isolation of cDNA clones containing the complete coding region of the human RED1 gene, and use of this sequence to determine the genomic structure from overlapping cosmids. Human RED1 spans approximately 25 kb and is composed of 10 exons containing coding sequences. The two RNA binding domains are located within a single large, 935 nucleotide, exon 2. An alternatively processed exon 6 potentially interrupts the catalytic domain. Exon 10 is largely composed of the 3' untranslated region, which is unusually high in GC content and contains a segment that is > 90% identical with the 3' UT of the homologous rat gene. A survey of expression patterns reveals differential processing of the 5 and 8.5 kb transcripts in all sources examined. The difference in transcript size likely results from alternative processing in the 3' UT. Potential relevance of overexpression of RED1 to the development of the Down Syndrome phenotype is discussed.

Adenosine Deaminase↗
PubMed1997

Efficiency of different grouping schemes for dust exposure in the European carbon black respiratory morbidity study.

OBJECTIVES: The aim of this study was to assess the theoretical efficiencies of different grouping strategies and its effect on the exposure-response relation in a study of respiratory morbidity associated with exposure to total inhalable and respirable carbon black dust. METHODS: A large epidemiological study is being undertaken to investigate the respiratory health of employees in the European carbon black manufacturing industry in relation to exposure to carbon black dust. In phase 2 of the study, repeated measurements of total inhalable and respirable dust were taken which enabled estimation of various components of variability in the exposure data (within and between worker variance and within and between group variance). These variance components were used to calculate the contrast in exposure between the groups in various classification schemes and to calculate the theoretical attenuation of the exposure-response relation and the standard error (SE) of the slope. RESULTS: High contrast in exposure was found when workers were classified according to the combination of their factory and job category as well as when these combinations were amalgamated into five exposure groups. Attenuation was minimal with most grouping schemes; only with the individual based strategy was the attenuation large. The SE of the theoretically attenuated exposure-response slope was smallest for the strategy based on individual people followed by the classification scheme based on factory and job category. CONCLUSIONS: It was concluded that, although some assumptions for the calculations of the attenuation of the exposure-response slope were not met, the most appropriate classification scheme of the worker seems to be by the combination of factory and job category.

Carbon↗