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E K Green

Publications and source records attributed to E K Green.

8 recordsLinked to original sources
PubMed2002

Are interleukin-1 gene polymorphisms risk factors or disease modifiers in AD?

Polymorphisms in the interleukin-1 genes, IL-1A and IL-1B, have been associated with AD, but not in all studies. The authors genotyped the IL-1A(-889) and IL-1B(-511) polymorphisms in large independent cohorts of 503 control individuals and 395 patients with AD, and a further 100 with brain Abeta load. No evidence was found of risk for AD with these variants, nor of an effect on age at onset. However, an impact of IL-1B(-511) on Abeta(40) load (p < 0.05) was detected.

Adult↗
PubMed2002

A polymorphism within intron 11 of the tau gene is not increased in frequency in patients with sporadic Alzheimer's disease, nor does it influence the extent of tau pathology in the brain.

There are numerous polymorphisms within the tau gene but these are in complete linkage disequilibrium and exist as two common extended haplotypes H1 and H2. We have investigated the frequency of these haplotypes in 83 cases of sporadic Alzheimer's disease (AD) using the +34 polymorphism in intron 11 of the tau gene as a marker of H1 and H2 haplotypes. The total amount of hyperphosphorylated tau protein (tau load), present as neurofibrillary tangles, neuropil threads or plaque neurites, was quantified in the frontal cortex of these patients and related to tau haplotype. We found no increase in H1H1 haplotype in this autopsy population of cases with AD compared to published control data. Stratification of cases for apolipoprotein E (APO E) genotype showed a slight, but not statistically significant, overrepresentation of epsilon 4 allele amongst bearers of H2 haplotype. There were no overall differences in tau load between haplotype groups though cases within each haplotype group bearing APO E epsilon 4 allele had a significantly higher tau load than those without epsilon 4 allele. Neither age at onset or duration of illness differed according to tau haplotype. We conclude that the frequency of tau gene H1 haplotype is not elevated in AD and possession of this has no impact upon the amount of tau pathology in AD.

Adult↗
PubMed2002

Evidence for familial cosegregation of major affective disorder and genetic markers flanking the gene for Darier's disease.

Darier's disease is a rare autosomal dominantly inherited keratosis.(1) We have previously reported a family in which major affective disorder co-segregated with Darier's disease, consistent with linkage between the Darier gene and a susceptibility locus for affective illness (max lod = 2.1).(2) The Darier gene has been mapped to 12q 23-q24.1 and identified as ATP2A2, a gene encoding SERCA2-a sarcoplasmic/endoplasmic reticulum calcium pump that plays a role in intracellular calcium signalling.(3) A number of groups have reported independent evidence of linkage between bipolar disorder and markers in this region.(4) We here describe a further Caucasian family of European origin in which there is co-occurrence of Darier's disease and major affective disorder including bipolar disorder and report the results of linkage analysis employing genetic markers flanking the Darier's gene. The pedigree includes two individuals with mood disorder from a branch of the family not affected with Darier's disease. However, there is a new mutation in the Darier (ATP2A2) gene in this family and all individuals affected by mood disorder show co-segregation with a haplotype in the region of the Darier's gene (max lod = 3.58). The family provides strong evidence against the Darier-causing mutation itself playing a major role in affective disorder but strongly supports the existence of a bipolar disorder susceptibility gene in the Darier region.

Bipolar Disorder↗
PubMed2000

Detailed mapping of a congenital heart disease gene in chromosome 3p25.

Distal deletion of chromosome 3p25-pter (3p- syndrome) produces a distinct clinical syndrome characterised by low birth weight, mental retardation, telecanthus, ptosis, and micrognathia. Congenital heart disease (CHD), typically atrioventricular septal defect (AVSD), occurs in about a third of patients. In total, approximately 25 cases of 3p- syndrome have been reported world wide. We previously analysed five cases and showed that (1) the 3p25-pter deletions were variable and (2) the presence of CHD correlated with the proximal extent of the deletion, mapping a CHD gene centromeric to D3S18. To define the molecular pathology of the 3p- syndrome further, we have now proceeded to analyse the deletion region in a total of 10 patients (five with CHD), using a combination of FISH analysis and polymorphic markers, for up to 21 loci from 3p25-p26. These additional investigations further supported the location of an AVSD locus within 3p25 and refined its localisation. Thus, the critical region was reduced to an interval between D3S1263 and D3S3594. Candidate 3p25 CHD genes, such as PMCA2 (ATP2B2), fibulin 2, TIMP4, and Sec13R, were shown to map outside the target interval. Additionally, the critical region for the phenotypic features of the 3p- phenotype was mapped to D3S1317 to D3S17 (19-21 cM). These findings will accelerate the identification of the 3p25 CHD susceptibility locus and facilitate investigations of the role of this locus in non-syndromic AVSDs, which are a common form of familial and isolated CHD.

Chromosome Mapping↗
PubMed1999

Genomic organization and chromosomal localization of the human CUL2 gene and the role of von Hippel-Lindau tumor suppressor-binding protein (CUL2 and VBP1) mutation and loss in renal-cell carcinoma development.

Germline mutations in the von Hippel-Lindau (VHL) disease tumor suppressor gene (TSG) convey a high risk of clear-cell renal-cell carcinoma (CC-RCC) and most sporadic CC-RCCs demonstrate somatic inactivation of the VHL TSG. However, the existence of further CC-RCC gatekeeper genes is implied by CC-RCC kindreds not linked to the VHL gene and the absence of somatic VHL inactivation in approximately 30% of sporadic CC-RCC. Genes that encode proteins which interact with the VHL gene product (VHL) provide candidate gatekeeper RCC genes. VHL forms a multimeric complex with two subunits (B and C) of the SIII (elongin) transcriptional elongation complex and CUL2, a member of the cullin family. Most pathogenic VHL mutations inhibit formation of the VHL/elonginB+C/CUL2 complex. A further VHL-binding protein of unknown function, VBP1, fails to bind to truncated forms of VHL. We have investigated the possible roles of CUL2 and VBP1 in renal tumorigenesis by analyzing sporadic RCC of known VHL mutation or hypermethylation status, including CC-RCC without VHL inactivation (n = 40); CC-RCC with VHL inactivation (n = 35); and non-CC-RCC (n = 14). No VBP1 mutations were identified in 89 sporadic RCCs, suggesting that VBP1 is not an RCC gatekeeper gene. To investigate CUL2, we mapped the CUL2 gene to chromosome band 10p11.1-p11.2, a region reported to show loss of heterozygosity (LOH) in several human cancers (including non-CC-RCC); determined the genomic organization; and performed mutation analysis of the 21 exons identified. Using novel intragenic polymorphisms, we detected LOH in 6/25 informative RCCs; however, no pathogenic CUL2 mutations were identified in the 89 RCCs analyzed. These findings suggest that unless CUL2 is inactivated by epigenetic events, it is not a major RCC TSG. However, CUL2 remains a candidate TSG for other tumor types demonstrating 10p LOH. Genes Chromosomes Cancer 26:20-28, 1999.

Carcinoma, Renal Cell↗
PubMed1996

The consistent association between Epstein-Barr virus and Hodgkin's disease in children in Kenya.

Recent studies have suggested that Epstein-Barr virus (EBV) may play a role in the etiology of Hodgkin's disease (HD). In a previous study, we used a latent membrane protein 1 (LMP1)-specific antibodies to examine archival material from 74 British children with HD and found 50% of cases to be positive. It is known that there are geographic and ethnic variations in the incidence of HD. We have investigated LMP1 status in formalin-fixed, paraffin wax-embedded lymph nodes with HD involvement from 53 children and 48 adults from Kenya using immunohistochemical staining. We also developed sensitive and specific in vitro gene amplification protocols for examining the EBV strain type in such material using several combinations of primers derived from the EBNA 2 and EBNA 3 coding regions. LMP1 positivity was present in 100% of the pediatric cases (two lymphocyte-predominant, 25 nodular sclerosis, 16 mixed cellularity, 5 lymphocyte depletion, and 5 unclassified) and in 66% of the adult cases (two of three lymphocyte-predominant, 26 of 39 nodular, sclerosis, two of two mixed cellularity, and two of four lymphocyte depletion). Tests to type the EBV strain were undertaken in 25 EBV-positive pediatric cases. A combination of type-specific polymerase chain reactions for EBNA 2 and EBNA 3C genes indicated that seven patients had type 1, eight had type 2, and 10 had dual infections with both types. Five cases with dual infections were further investigated using a sensitive in situ hybridization for the EBV-encoded, small nuclear nonpolyadenylated RNAs (EBERs). EBER transcripts were detected in Reed-Sternberg and Hodgkin cells and in occasional infiltrating lymphocytes. These observations indicate that in Kenya EBV is consistently associated with pediatric cases of HD, and that biopsies from a number of such cases appear to carry both type 1 and type 2 viral sequences.

Adolescent↗
PubMed1991

Detection of human apolipoprotein E3, E2, and E4 genotypes by an allele-specific oligonucleotide-primed polymerase chain reaction assay: development and validation.

A polymerase chain reaction (PCR) assay has been developed and validated by using allele-specific oligonucleotide (ASO) primers to specifically amplify E3, E2, and E4 polymorphic sequences of the human apolipoprotein E (apo E) genes. Degenerate ASOs containing one or two additional 3' mismatches provided greater specificity than did ASOs containing a single mid-sequence or 3' allele-specific mismatch with plasmid pEB4 or genomic DNA as template. Optimal specificity and efficiency of amplification did not correlate with primer annealing conditions, whether determined theoretically or via oligo-melting experiments. Pre-cycling denaturation times and high cycling denaturation temperatures were also required for optimal amplification, presumably because of the high G:C content (75-85%) of apo E gene sequences. Conditions permissive for amplification and discrimination with plasmid DNA did not transpose favorably to amplification from human genomic DNA from peripheral blood leukocytes; the latter required nested primer reactions. These data may be valuable in predicting PCR assay conditions for other G:C-rich sequences containing polymorphic sequence differences. The assay described is both more accurate and rapid (24 h) than previously described methods for phenotyping or genotyping human apo E from blood specimens.

Alleles↗