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At least 1,189 records · Page 66Linked to original sources
PubMed2000

Mutation of p53 with loss of heterozygosity in the osteosarcomatous component of a dedifferentiated chondrosarcoma.

We investigated a dedifferentiated chondrosarcoma of a 61-year-old woman with an osteosarcomatous high-grade component for p53 alteration. The low-grade cartilaginous and the high-grade osteosarcomatous components of the tumor were macrodissected and evaluated separately by immunohistochemistry and molecular biology. We used PCR-SSCP analysis and direct sequencing to screen exons 4-8 for p53 mutations. The p53 intron 1-polymorphism was investigated for loss of heterozygosity. A functionally relevant p53 missense mutation in codon 193 of exon 6 (A-to-T transversion) with loss of wild-type allele was detected only in the dedifferentiated component. Using the monoclonal antibody DO-1, immunohistochemistry failed to show p53 overexpression. This evidence of p53 mutation may be regarded as at least a co-factor that "switched" the preexisting low-grade conventional chondrosarcoma to a highly malignant dedifferentiated tumor.

Chemotherapy, Adjuvant↗
PubMed1997

Molecular basis of variegate porphyria: a de novo insertion mutation in the protoporphyrinogen oxidase gene.

The porphyrias are disorders that result from the inherited or acquired dysregulation of one of the eight enzymes in the heme biosynthetic pathway. Variegate porphyria (VP) is characterized by deficiencies in protoporphyrinogen oxidase (PPO) and has recently been genetically linked (Z = 6.62) to the PPO gene on chromosome 1q21. In this study, we have identified two sequence variants in the PPO gene in a family with VP. The first is a neutral polymorphism at the -47 position of intron 2; this polymorphism is present in the general population and is unlikely to underlie the VP phenotype. The second is a mutation in the PPO gene in a patient with VP; the mutation consists of an apparently de novo 2-bp insertion in exon 3 of PPO and results in a frameshift and downstream premature termination codon. These data establish that a frameshift mutation in PPO is the underlying mutation in this patient with VP and explain the sporadic occurrence of the phenotype in this family.

Adult↗
PubMed1998

Exclusion of five subunits of cGMP phosphodiesterase in Leber's congenital amaurosis.

Leber's congenital amaurosis (LCA) is the earliest and most severe of all inherited retinal dystrophies. Recently, we mapped an LCA gene to chromosome 17p13.1 (LCA1) and ascribed the disease to mutations of the retinal guanylate cyclase (ret GC) gene in a subset of families of North African ancestry. Owing to the genetic heterogeneity of LCA and considering that LCA1 results from an impaired production of cGMP in the retina (with permanent closure of cGMP-gated cation channels), we hypothesized that the activation of the cGMP phosphodiesterase (PDE) could trigger the disease by lowering the intracellular cGMP level in the retina. The rod and cone cGMP-PDE inhibitory subunits were regarded therefore as candidate genes in LCA. Here, we report the exclusion of five rod and cone cGMP-PDE subunits in LCA families unlinked to chromosome 17p13.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2003

Polymorphism in the peroxisome proliferator-activated receptor alpha gene influences the risk for Alzheimer's disease.

The peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a member of the steroid hormone super family of ligand-inducible transcription factors, involved in glucose and lipid metabolism. We screened for polymorphisms in the PPAR-alpha gene and detected two known polymorphisms located in exon 5 and intron 7. These polymorphisms were investigated for their possible association with Alzheimer's disease (AD) and for their effect in carriers of an insulin gene (INS) polymorphism. The PPAR-alpha C --> G polymorphism in exon 5 (L162V) was associated with AD, in that the V-allele was more frequent in AD patients than in healthy subjects. Further data analysis revealed that carriers of an PPAR-alpha L162V V-allele and an INS-1 allele presented with an increased risk for AD. Cerebrospinal fluid amyloid-beta levels were influenced by PPAR-alpha L162V genotype. These results suggest, that PPAR-alpha polymorphism may be a risk factor for AD.

Aged↗
PubMed2005

Oxidative stress related markers in the "VITA" and the centenarian projects.

Oxidative stress seems to play an important role in the pathophysiology of Alzheimer's disease (AD). At present there are no easily accessible biochemical markers for AD. We performed activity assays for platelet MAO-B and erythrocyte Cu/Zn-SOD as well as Western blotting for these two proteins. Moreover, we assessed plasma lactoferrin and performed RFLP-analysis for the MAO-B-intron-13-polymorphism in patients from the Vienna-Transdanube Aging (VITA) and from the so called centenarian project. The first one, VITA, is a community-based cohort study of all 75 years old inhabitants of a geographical region of Vienna. The centenarian project investigates chronic care in-old patients suffering from AD. In both sexes platelet MAO-B activity increased significantly in the AD group, and Cu/Zn-SOD activity decreased, but the latter effect was significant only in females. No significant difference was found regarding plasma lactoferrin. No correlation was found between MAO-Bi13 and MAO-B platelet activity or allele MAO-Bi13 and disease frequency. These results point to the possibility that a combination of MAO-B and SOD activity levels might be useful tools for an early diagnosis of AD.

Aged↗
PubMed1996

Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family.

The mutated gene responsible for the tubby obesity phenotype has been identified by positional cloning. A single base change within a splice donor site results in the incorrect retention of a single intron in the mature tub mRNA transcript. The consequence of this mutation is the substitution of the carboxy-terminal 44 amino acids with 24 intron-encoded amino acids. The normal transcript appears to be abundantly expressed in the hypothalamus, a region of the brain involved in body weight regulation. Variation in the relative abundance of alternative splice products is observed between inbred mouse strains and appears to correlate with an intron length polymorphism. This allele of tub is a candidate for a previously reported diet-induced obesity quantitative trait locus on mouse chromosome 7.

Adaptor Proteins, Signal Transducing↗
PubMed1997

The genetics of Alzheimer's disease.

Alzheimer's disease (AD) is the major cause of dementia in the U.K. The clinical diagnosis of the specific disease resulting in dementia is unreliable and thus a definitive diagnosis of AD is best made in conjunction with post-mortem findings of amyloid plaques and neurofibrillary tangles. Alzheimer's disease is neuropathologically indistinguishable in the young and old, but has been divided arbitrarily into early- and late-onset disease using age cut-offs of 60 or 65 years. Twin and family studies suggest that genetic factors play a major role in its aetiology. This review considers the three loci which have been shown to be associated with early-onset AD: amyloid precursor protein, presenilin (PS)-1 and PS-2. Mutations in these genes seem to be associated with overproduction of the 42-amino acid form of beta-amyloid, suggesting that this may be a central pathological process in AD. The impact of the different apo E alleles on the risks for late- and early-onset AD is discussed and compared with other dementing conditions. Recent analyses suggest that there are likely to be other genes besides apo E which impact on late-onset AD risk. The possible roles in AD of the mitochondrial mutation at position 4336, the PS intron 8 polymorphism, and variants in the alpha 1-antichymotrypsin and VLDL-receptor genes, are considered.

Alzheimer Disease↗
PubMed1998

Association of a variable number of tandem repeats in the endothelial constitutive nitric oxide synthase gene with essential hypertension in Japanese.

An impaired synthesis of nitric oxide (NO) by the vascular endothelium has been implicated in the pathogenesis of essential hypertension (EH). The possible association between a variable number of tandem repeats (VNTR) polymorphism in intron 4 of the endothelial constitutive NO synthase (ecNOS) gene and EH in Japanese subjects was investigated. A total of 123 individuals with EH and 120 normotensive control subjects were studied. The VNTR region of the ecNOS gene was amplified by the polymerase chain reaction to determine the number of repeats, and the allele frequencies were compared between the hypertensive and normotensive groups. Two alleles, containing four and five repeats, were identified. The overall distributions of allele frequencies differed significantly between the two groups, with the four-repeat allele more frequent in the EH group than in the normotensive group (P = .00027, odds ratio = 4.0). The four-repeat allele of the ecNOS gene was thus associated with EH and may be a genetic marker of this disease in Japanese subjects.

Alleles↗
PubMed2004

Long-range (17.7 kb) allele-specific polymerase chain reaction method for direct haplotyping of R117H and IVS-8 mutations of the cystic fibrosis transmembrane regulator gene.

Genotyping of genetic polymorphisms is widely used in clinical molecular laboratories to confirm or predict diseases due to single locus mutations. In contrast, very few molecular methods determine the phase or haplotype of two or more mutations that are kilobases apart. In this report, we describe a new method for haplotyping based on long-range allele-specific PCR. Reaction conditions were established to circumvent the incompatibility of using allele-specific primers and a polymerase with proofreading activity. Haplotypes are determined by post-PCR analysis using different detection methods. The clinical application presented here directly determines the phase of two mutations separated by 17.7 kilobases in the cystic fibrosis transmembrane conductance regulator gene. Each mutation, the missense mutation R117H in exon 4 and the 5T polymorphism in intron 8 (IVS-8), have mild phenotypic effect unless they are present on the same chromosome (in cis). If an individual is heterozygous for both R117H and the IVS-8 5T variant, cis/trans testing is required to completely interpret results. The molecular method presented here bypasses the need to perform family studies to establish haplotypes. We propose use of this assay as a reflex clinical test for R117H- 5T-positive samples.

Alleles↗
PubMed1999

Lack of an intronic Sp1 binding-site polymorphism at the collagen type I alpha1 gene in healthy Korean women.

Osteoporosis is a disease that is strongly genetically influenced. However, the genes responsible for the disease are poorly defined. Recent data show that a G-T transition polymorphism of the Sp1 binding site at the collagen type I alpha1 gene (Sp1 polymorphism) is associated significantly with bone mineral density (BMD) and osteoporotic fracture in British women. To establish the association between the Sp1 genotypes and BMD in Korean women, we examined 200 healthy postmenopausal women of Korean ethnicity, ranging in age from 44 to 66 years (mean+/-SD: 54.7+/-5.3 years). PCR amplification using the same primers as those used previously, with enzyme digestion, revealed no restriction site in our samples. We also performed a single-strand conformational polymorphism (SSCP) analysis in 100 of the 200 samples and could not find any polymorphic sites in the PCR amplification region. Based on our study, the Sp1 polymorphism at the type I collagen alpha1 gene was not found in Korean women. Therefore, we suggest that the Sp1 polymorphism at the type I collagen alpha1 gene is absent or rare in Korean women. Based on the present findings, this polymorphism does not seem to be responsible for the entire genetic contribution to BMD.

Adult↗
PubMed1999

Protein binding to simple repetitive sequences depends on DNA secondary structure(s).

Simple repetitive DNA sequences are ubiquitous constituents of eukaryotic chromosomes. The properties of simple repeats generate increased interest as expansions of certain trinucleotide blocks cause human diseases. We studied protein binding and structural features of (gaa x ttc)n tracts e.g. in the polymorphic frataxin intron 1 and (gt)n(ga)m stretches from different HLA-DRB1 alleles in their original genomic environments. Electrophoretic mobility shift assays revealed that HeLa nuclear proteins bind to DNA fragments containing these simple repeat blocks. The major retarded protein/DNA complexes comprise, in both cases, zinc-dependent proteins present in nuclear extracts from different cell types. Competition experiments using various simple repeats differing in length and flanking regions demonstrate specific interactions. DNase I footprinting shows protein-binding sites located either within the repeats alone or within the repeats as well as their flanking regions, often with preference for one strand. Comparing different (gt)n(ga)m alleles, a regular pattern of footprints was not detectable in the (gt)n part indicating that the zinc-dependent protein recognizes structural rather than sequence-specific features. OsO4 and DEPC modifications followed by electrophoretic and electron microscopical analyses demonstrate that the homopurine blocks often form different types of intramolecular triple helices. A similar situation was evident using (gaa x ttc)n blocks of different lengths within frataxin intron 1 as targets. These data have functional implications for non-coding (gaa x ttc)n and (gt)n(ga)m tracts with regard to gene expression in vivo.

Animals↗
PubMed2016

17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells.

Asthma and autoimmune disease susceptibility has been strongly linked to genetic variants in the 17q21 haploblock that alter the expression of ORMDL3; however, the molecular mechanisms by which these variants perturb gene expression and the cell types in which this effect is most prominent are unclear. We found several 17q21 variants overlapped enhancers present mainly in primary immune cell types. CD4+ T cells showed the greatest increase (threefold) in ORMDL3 expression in individuals carrying the asthma-risk alleles, where ORMDL3 negatively regulated interleukin-2 production. The asthma-risk variants rs4065275 and rs12936231 switched CTCF-binding sites in the 17q21 locus, and 4C-Seq assays showed that several distal cis-regulatory elements upstream of the disrupted ZPBP2 CTCF-binding site interacted with the ORMDL3 promoter region in CD4+ T cells exclusively from subjects carrying asthma-risk alleles. Overall, our results suggested that T cells are one of the most prominent cell types affected by 17q21 variants.

Asthma↗
PubMed1997

Comparative anchor tagged sequences (CATS) for integrative mapping of mammalian genomes.

Precise comparisons of mammalian gene maps require common anchor loci as landmarks for conserved chromosomal segments. Using a computer script that automates DNA sequence database alignments, we designed 410 evolutionarily conserved primer pair sequences which are specific for anchor locus gene amplification from any mammalian species' DNA. Primer pairs were designed to span introns for polymorphism ascertainment, and to include sufficient exonic sequence (25-400 bp) to allow for gene identification. A total of 318 primer pairs were optimized for domestic cats, and 86% of the sequenced feline PCR products showed homology to the gene of primer origin. A screen of 20 mammals from 11 orders revealed that 35-52% of the 318 primers yielded a single PCR product without further optimization suggesting that nearly 75% can be optimized for any eutherian mammal.

Animals↗
PubMed2002

Surfactant protein B gene variations enhance susceptibility to squamous cell carcinoma of the lung in German patients.

Genetic factors are thought to influence the risk for lung cancer. Since pulmonary surfactant mediates the response to inhaled carcinogenic substances, candidate genes may be among those coding for pulmonary surfactant proteins. In the present matched case-control study a polymorphism within intron 4 of the gene coding for surfactant specific protein B was analysed in 357 individuals. They were divided into 117 patients with lung cancer (40 patients with small cell lung cancer, 77 patients with non small cell lung cancer), matched controls and 123 healthy individuals. Surfactant protein B gene variants were analysed using specific PCR and cloned surfactant protein B sequences as controls. The frequency of the intron 4 variation was similar in both control groups (13.0% and 9.4%), whereas it was increased in the small cell lung cancer group (17.5%) and the non small cell lung cancer group (16.9%). The gene variation was found significantly more frequently in patients with squamous cell carcinoma (25.0%, P=0.016, odds ratio=3.2, 95%CI=1.24-8.28) than in the controls. These results indicate an association of the surfactant protein B intron 4 variants and/or its flanking loci with mechanisms that may enhance lung cancer susceptibility, especially to squamous cell carcinoma of the lung.

Adult↗
PubMed2000

Mapping of the chicken immunoglobulin heavy-chain constant region gene locus reveals an inverted alpha gene upstream of a condensed upsilon gene.

Chicken antibodies are increasingly being used as diagnostic and therapeutic tools. As only the genomic organization of the micro encoding gene was previously known, we analysed the chicken immunoglobulin Y (IgY) and IgA (upsilon and alpha chain) immunoglobulin heavy-chain constant region (IGHC) genes and the organization of the chicken IGHC locus. The alpha gene is encoded by four separate exons, whereas, surprisingly, there is no intervening DNA sequence between the CH1 and CH2 domains of the IgY heavy chain, which is thus encoded by three exons separated by two introns. DNA sequence analysis shows that the exon boundaries of the chicken IGHC genes are not consistent with published domain borders. Furthermore, differences in DNA sequence confirm the existence of IgY, IgA and IgM allotypes in chickens. Finally, our results show that the IGHC genes of chicken (IgY, IgA and IgM) are all colocated on chromosome E18C15W15, where the alpha gene is located upstream of the upsilon gene in an inverted transcriptional orientation. The distances between the mu and alpha genes and the alpha and upsilon genes are about 18 and 15 kilobases, respectively, and thus, the size of the whole chicken IGHC locus is approximately 67 kilobases.

Animals↗