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At least 739 records · Page 41Linked to original sources
PubMed1999

Linkage analysis of endothelial nitric oxide synthase gene with human blood pressure.

OBJECTIVE: Endothelial nitric oxide exerts important effects on the regulation of vascular tone and structure. Variants of the endothelial nitric oxide synthase gene (eNOS) have been associated with hypertension and myocardial infarction, although some reports have shown negative linkage with hypertension. To examine whether the region encoding the eNOS gene is linked with physiological blood pressure variation, we undertook a linkage analysis of this region in the general population. DESIGN: In healthy volunteer families, we used two independent quantitative linkage analyses to examine the relationship between genotypes and phenotypes, with both parametric and non-parametric and single-locus and multi-point methods. METHODS: We selected 260 families comprising mother and father (aged 40-70 years) and two natural offspring (aged 18-30 years) from the Victorian Family Heart Study. After standardized measurement of clinical data and extraction of DNA, all family members were genotyped at five microsatellite loci including the CA repeat in the eNOS gene by a PCR method. The quantitative linkage analyses were conducted according to two different analysis programs, the Genetic Analysis System (GAS) and the MAPMAKER/SIBS. RESULTS: With both linkage analyses, we found no linkage between any of the loci on chromosome 7q35-36 and the phenotypes systolic and diastolic blood pressure, mean arterial pressure, pulse pressure, pulse rate, weight, height and body mass index. CONCLUSION: Based on these results, we conclude that in this population the eNOS gene is not linked to the physiological variation of blood pressure and other related phenotypes.

Adult↗
PubMed1999

Polymorphism of the human alcohol dehydrogenase 4 (ADH4) promoter affects gene expression.

The human alcohol dehydrogenase 4 gene (ADH4) encodes the human pi-alcohol dehydrogenase (pi-ADH), which can contribute to ethanol metabolism at moderate and high concentrations of ethanol. There are no known structural variants of pi-ADH in humans. We report the first polymorphisms in the ADH4 gene, at three sites in the promoter: -192 bp, -159 bp and -75 bp, respectively. To determine whether these variations affected promoter function, different haplotypes of the ADH4 proximal promoter were subcloned into a luciferase reporter vector, and the relative promoter activity analysed in hepatoma cells. One of the three sites had a dramatic effect on promoter activity, while the others did not detectably affect activity. The -75A allele had promoter activity more than twice that of the -75C allele. Alcohol dehydrogenase activity is rate limiting for ethanol oxidation. We hypothesize that the different ADH4 alleles lead to different amounts of pi-ADH in liver, which affects the risk for alcoholism by modulating alcohol metabolism.

Alcohol Dehydrogenase↗
PubMed1997

High density lipoprotein and coronary heart disease: insights from mutations leading to low high density lipoprotein.

Hypoalphalipoproteinemia can result from defects in the genes encoding apolipoprotein A-I, the major protein component of HDL, or enzymes that are critical for the formation/maturation of mature HDL. Recent information contradicts earlier findings, suggesting that most of the affected subjects are at increased risk of developing coronary heart disease, independent of the mutated gene. A possible exception is represented by mutations in the apolipoprotein A-I gene leading to structural variants, that might even exert a protective effect against atherosclerosis.

Apolipoprotein A-I↗
PubMed2025

The landscape of structural variation in pediatric cancer.

Structural variants (SVs) account for over 60% of the driver variants in pediatric cancer, and in many cases act as the cancer initiating event. To study SVs from a pan-cancer perspective, we analyzed 1,616 pediatric cancer genomes in 16 major cancer types of hematological malignancies (n = 908), brain tumors (n = 183), and solid tumors (n = 525) and compared their profiles to those of 2,203 adult cancers. The SV burden varied ~100-fold across pediatric cancer types and demonstrated an 8- to 16-fold reduction compared to adult brain and solid tumors but was comparable in pediatric versus adult hematological malignancies. Recurrent SV hotspots occurred uniquely in pediatric acute lymphoblastic leukemias (ALLs) in proximity to RAG-mediated recombination signal sequences (RSS) and disrupted multiple immune-related loci as well as 69 genes, which often involved cryptic RSS sites. By contrast, such hotspots affected only immune-related loci but not driver genes in adult lymphoid cancers. Eight SV signatures extracted from the cohort had varying distributions across cancer types, with clustered translocations reflecting templated insertions in osteosarcoma, and medium-sized deletions (10 kb to 1 Mb) enriched in cancers with RAG-mediated deletions. Intra-patient evolutionary analysis in 13 patients with multiple spatiotemporally distinct samples revealed that RAG-mediated recombination in leukemia and complex rearrangements in solid tumors occurred both early in disease initiation and continuously during later diversification, contributing to clonal heterogeneity. Finally, we found that both driver genes and fragile sites were the two genomic regions most frequently disrupted by SVs. The unique and diverse SV landscapes that emerged from this comprehensive analysis expand the scope of RSS-mediated mutagenesis in pediatric ALL and will be a valuable resource for guiding future functional studies and the design of clinical genomic testing in pediatric cancer.

Journal Article↗
PubMed2025

Discrete Subdomains Establish Epigenetic Diversity in Subtelomeric Heterochromatin.

Subtelomeres are imperfect repeats adjacent to telomeres that are repressed by heterochromatin. Although essential for genome integrity, their repetitive nature has thwarted dissection of local heterochromatin assembly and maintenance mechanisms. Here, we engineered Schizosaccharomyces pombe strains carrying fluorescent reporters at a single subtelomere. We find that subtelomeric heterochromatin is organized into discrete subdomains that nucleate at telomere-proximal and cryptic internal sites. Telomere-proximal regions depend on canonical shelterin or RNA interference nucleation pathways, while telomere-distal regions require nucleosome remodelers, histone chaperones, and boundary-associated factors. Using multi-generational live imaging and targeted perturbations, we show that subtelomeric subdomains display position-specific, clonally variable silencing across a spectrum of robust to fragile epigenetic states. This clonal variegation is also induced by naturally occurring subtelomeric structural variants. These findings demonstrate that subtelomeric heterochromatin maintenance is not uniform but rather governed by local chromatin context and architecture.

H3K9 methylation↗
PubMed2026

MRE11 suppresses germline mutagenesis at meiotic double-strand breaks in mice.

SPO11 forms hundreds of double-strand breaks (DSBs) to initiate meiotic recombination that is normally error-free. However, SPO11 activity can be mutagenic when one chromatid incurs closely spaced DSBs (double cuts), especially when DSBs are dysregulated by loss of the ATM kinase. De novo indels and structural variants can arise via end joining at double cuts within a single hotspot (microdeletions) or at adjacent hotspots separated by at least 30 kb, as we now show, sometimes accompanied by ectopic insertions of double-cut fragments. Here, we investigate how meiotic DSB end processing influences end joining. In MRE11-deficient mouse spermatocytes, which do not resect their DSBs, deletions at double cuts occur readily, with end-joining breakpoint profiles closely matching SPO11 DSB profiles. Microdeletions suggest that two DSBs can be as close as ∼21 bp. The tyrosyl-DNA phosphodiesterase TDP2 contributes to both deletion formation and ectopic insertion of double-cut fragments, presumably by removing SPO11 from DNA ends prior to joining. Finally, observations suggest a cooperative role for MRE11 and ATM in locally regulating DSB distributions. Our findings provide insight into the mechanism of de novo mutation origin, emphasizing the role of meiotic DSBs in shaping genome evolution.

Animals↗
PubMed2005

A genome-wide survey of structural variation between human and chimpanzee.

Structural changes (deletions, insertions, and inversions) between human and chimpanzee genomes have likely had a significant impact on lineage-specific evolution because of their potential for dramatic and irreversible mutation. The low-quality nature of the current chimpanzee genome assembly precludes the reliable identification of many of these differences. To circumvent this, we applied a method to optimally map chimpanzee fosmid paired-end sequences against the human genome to systematically identify sites of structural variation > or = 12 kb between the two species. Our analysis yielded a total of 651 putative sites of chimpanzee deletion (n = 293), insertions (n = 184), and rearrangements consistent with local inversions between the two genomes (n = 174). We validated a subset (19/23) of insertion and deletions using PCR and Southern blot assays, confirming the accuracy of our method. The events are distributed throughout the genome on all chromosomes but are highly correlated with sites of segmental duplication in human and chimpanzee. These structural variants encompass at least 24 Mb of DNA and overlap with > 245 genes. Seventeen of these genes contain exons missing in the chimpanzee genomic sequence and also show a significant reduction in gene expression in chimpanzee. Compared with the pioneering work of Yunis, Prakash, Dutrillaux, and Lejeune, this analysis expands the number of potential rearrangements between chimpanzees and humans 50-fold. Furthermore, this work prioritizes regions for further finishing in the chimpanzee genome and provides a resource for interrogating functional differences between humans and chimpanzees.

Animals↗
PubMed1995

Expression of Phospholipase D during Castor Bean Leaf Senescence.

Membrane deterioration in plant senescence is commonly associated with progressive decreases in membrane phospholipid content. This study investigated the expression and regulation of phospholipase D (PLD; EC 3.1.4.4) during senescence in castor bean (Ricinus communis L. cv Hale) leaf discs. The rate of leaf senescence was accelerated by 50 [mu]M abscisic acid and was attenuated by 50 [mu]M cytokinin during incubation at 23[deg]C for up to 5 d. Leaf senescence was indicated by decreases in the content of total proteins, chlorophyll, and phospholipids. PLD activity in both membrane-associated and cytosolic fractions showed a gradual increase in the absence of phytohormones. Abscisic acid stimulated an increase in membrane-associated PLD and had little effect on the soluble form. On the other hand, cytokinin retarded the increase in membrane-associated PLD. Immunoblotting analysis using PLD-specific antibodies revealed that the changes in PLD activity were correlated with those of PLD protein. Analysis of PLD by nondenaturing PAGE showed the appearance of a PLD structural variant, PLD 3, in abscisic acid-treated leaf discs. Northern blotting analysis using a PLD cDNA probe revealed an increase in PLD mRNA in senescing leaf discs. These data indicate complex mechanisms for the regulation of PLD during senescence, which include increases in membrane-associated PLD, differential expression of PLD isoforms, and changes in amounts of PLD protein and mRNA. Such controlled expression points to a role for PLD in membrane deterioration and plant senescence.

Journal Article↗
PubMed2004

Emerging functions of gonadotropin-releasing hormone II in mammalian physiology and behaviour.

Gonadotropin-releasing hormone (GnRH) is the central neuroendocrine regulator of the hypothalamic-pituitary-gonadal axis. Multiple structural variants of GnRH are present in vertebrates. The first isoform isolated in the mammalian brain (GnRH I) was shown to regulate the release of pituitary gonadotropins. Recently, a second form has been discovered in mammals (GnRH II), both in the brain and periphery. Although it is unlikely to be a primary regulator of gonadotropin release, the highly conserved GnRH II variant appears to have a wide array of physiological functions. In the periphery, GnRH I and II have similar roles in regulating cell proliferation and mediating hormonal secretion from the ovary and placenta in an autocrine/paracrine manner. In the brain, GnRH I and II apparently modulate mammalian reproductive behaviours in different but complementary ways: GnRH I stimulates luteinizing hormone/follicle-stimulating hormone secretion (and thus gonadal steroids) and promotes sexual behaviour in ad libitum fed animals. By contrast, GnRH II acts as a permissive regulator of female reproductive behaviour based on energy status, as well as a modifier of short-term food intake. GnRH II has also been implicated in the regulation of calcium and potassium channels in nervous systems of amphibians, functions which may also be present in mammals. Increasing evidence suggests that the effects of GnRH II in both the periphery and brain may be mediated by GnRH receptor subtypes distinct from the type-1 GnRH receptor. It is likely that this evolutionarily conserved peptide has been co-opted over evolutionary time to possess multiple regulatory functions in a broad range of biological aspects, including, but not limited to, reproduction. Here, the proposed actions of both neural and peripheral GnRH II in affecting physiology and behaviour are summarized, and an outline of critical directions for future research is proposed.

Animals↗
PubMed2005

Evidence that the type-2 gonadotrophin-releasing hormone (GnRH) receptor mediates the behavioural effects of GnRH-II on feeding and reproduction in musk shrews.

Gonadotrophin-releasing hormone (GnRH) is a regulatory neuropeptide of which there are multiple structural variants. In mammals, a hypothalamic form (GnRH-I) controls gonadotrophin secretion whereas a midbrain form (GnRH-II) appears to have a neuromodulatory role affecting feeding and reproduction. In female musk shrews and mice, central administration of GnRH-II reinstates mating behaviour previously inhibited by food restriction. In addition, GnRH-II treatment also decreases short-term food intake in musk shrews. GnRH-II can bind two different mammalian GnRH receptors (type-1 and type-2), and thus it is unclear which receptor subtype mediates the behavioural effects of this peptide. Adult female musk shrews implanted with i.c.v. cannula were food restricted or fed ad lib and then tested for sexual behaviour or food intake. One hour before testing, animals were pretreated with vehicle or Antide, a potent type-1 GnRH receptor antagonist (at a dose that blocks GnRH-I or -II mediated ovulation). Twenty minutes before testing, females were infused a second time with either GnRH-II or vehicle. Additional females were tested after an infusion of 135-18, a type-1 receptor antagonist that displays agonist actions at the primate type-2 receptor. GnRH-II treatment increased sexual behaviour in underfed female shrews; pretreatment with Antide did not block this action, suggesting that the effects of GnRH-II are not mediated via the type-1 receptor. Similarly, the inhibitory effects of GnRH-II on short-term food intake were not prevented by pretreatment with Antide. The behavioural effects of the type-2 receptor agonist 135-18 were similar to those seen in GnRH-II-treated females, with 135-18 promoting sexual behaviour and decreasing food intake. Collectively, these results indicate that GnRH-II does not act via the type-1 GnRH receptor to regulate mammalian behaviour but likely activates the type-2 GnRH receptor.

Animals↗
PubMed1991

Genetic diversity among the T-protein genes of group A streptococci.

T protein is a trypsin- and pepsin-resistant molecule on the surface of group A streptococci used as a serological tool to differentiate streptococci of this group. The purpose of this study was to determine the relatedness among the T protein genes of the 25 known T serotypes. DNA probes were constructed which represented various regions of the structural gene for the T6 protein, tee6. The probes were assayed for their ability to hybridize HindIII digests of chromosomal DNA from the 25 different T serotypes. Probe pTEE6.3, coding for the entire T6 protein, and pTEE6(1-299), coding for the amino-terminal half of T6, displayed the highest amount of homology, each binding to 10 of 25 T serotypes. Probes coding for sequences in the carboxy-terminal half of T6 showed considerably less homology among T serotypes with one probe hybridizing with only three out of 25. A synthetic oligonucleotide coding for the carboxy-terminal hydrophobic domain of T6, an area conserved to some degree among several bacterial surface proteins, showed homology with only seven out of 25 T serotypes. Hybridization with sequences outside the tee6 coding area provided additional information on the relatedness of certain sets of T serotypes according to restriction-fragment size heterogeneity. Clearly, there is considerable diversity among T-serotype genes. The data suggest that two or more families of structurally variant T proteins exist, which share only the property of proteolytic resistance and/or, perhaps, some biological function.

DNA Probes↗
PubMed1988

A cytotoxic human-human hybridoma antibody (TrH6) specific for HLA-DRw52.

TrH6 is a new human-human hybridoma antibody (Ab) of IgM, lambda isotype. At concentrations of 17-5000 ng IgM/ml, TrH6 killed twelve out of fourteen lymphoblastoid cell lines that expressed DRw52, but none of the nine DRw53 homozygous lines. Both DRw52+ cells (LUY, TAB) not killed by TrH6 were DR8+, suggesting that these lines express a structural variant of DRw52 linked to DR8. The murine cytotoxic DRw52-specific mAb 7.3.19.1 (Koning et al. 1984) exhibited the same pattern of reactivity with DRw52+ cells as TrH6. However, unlike TrH6, 7.3.19.1 cross-reacted weakly with two DR7+DRw53+ homozygous cell lines, suggesting that the TrH6 epitope has a more limited distribution. The reactions with a panel of cells with known deletions in the HLA-region supported the conclusion that TrH6 is specific for DRw52. Further evidence was obtained in a competition RIA, where the murine mAbs L243 (anti-DR monomorphic) and 7.3.19.1 (anti-DRw52) inhibited binding of radiolabeled TrH6 to DRw52 homozygous cells. TrH6-coated magnetic beads provided a simple rosette-assay for typing of "buffy-coat" leukocytes for the TrH6 epitope.

Antibodies, Monoclonal↗
PubMed1990

Three human interferon-alpha 2 subvariants disclose structural and functional differences.

The human interferon-alpha 2 subvariants 2a, 2b and 2c differ by only one or two amino acids at positions 23 and/or 34 of the mature protein. In this study, the coding regions of the three interferon-alpha 2 subvariants were derived from the cDNA of interferon-alpha 2c by site-directed in vitro mutagenesis. The interferon-alpha subvariants were synthesized using the same Escherichia coli strain for production and were subsequently purified. Comparative studies revealed that they differ significantly in their biological and antigenic properties. Therefore, amino acid positions 23 and 34 seem to be crucial for structure/function of human interferon-alpha. Furthermore, the study points to the importance of defining, whether such minor structural variants of naturally occurring polypeptides represent functional variants.

Amino Acids↗
PubMed1991

Atrial natriuretic peptide (ANP) is a high-affinity substrate for rat insulin-degrading enzyme.

A cytosolic protein specifically binding to and degrading atrial natriuretic peptide (ANP) was purified from rat brain homogenate. Based on partial amino acid sequences and enzymatic properties, this protein with an apparent molecular mass of 112 kDa has been identified as the rat insulin-degrading enzyme (IDE). In addition to the known substrates, insulin and transforming-growth-factor alpha IDE binds also with high affinity (apparent Kd 60 nM) to ANP. Competition studies with structural variants of ANP demonstrate that both the C terminus and the disulfide loop of the molecule are essential for high-affinity binding. The data suggest that IDE might be involved in the cellular processing and/or metabolic clearance of ANP.

Affinity Labels↗
PubMed1995

Association of Hb S/Hb lepore and delta beta-thalassemia/Hb lepore in Sicilian patients: review of the presence of Hb lepore in Sicily.

The hemoglobin (Hb) lepore-Boston is a beta-globin structural variant, produced in a reduced amount and formed from the fusion of N-terminus delta-(residues 1-87) and C-terminus beta-chains (residues 116-146). This type of fusion protein is quite common in Southern Italy (Campania, Calabria, and Sicily). We report here the hematological and hemoglobin data on 96 unrelated Sicilians with Hb lepore trait. Particularly interesting are the subjects where Hb lepore occurs with Hb S or Sicilian type delta beta-thalassemia. In these individuals, striking features are clinical variability and different hematological pictures. These observations underscore the importance of thalassemia screening in these geographic areas, such as Southern Italy, principally Sicily, where the mutations in globin gene clusters are especially prevalent. Moreover, as from the second half of the last century, owing to high migratory flux from Sicily to Northern Europe, North and South America, and Australia, the Hb lepore, as well as other hemoglobin variants, have become prevalent, making the identification of the heterozygotes a problem of general interest.

Adolescent↗
PubMed1985

The structure and genetics of the C2 and factor B genes.

This review summarises our current knowledge of the genetic organisation, structure and polymorphism of the loci for the complement proteins, C2 and Factor B--class III gene products of the major histocompatibility complex. cDNA probes specific for C2 and Factor B have been used to screen cosmid libraries of human genomic DNA, and this has allowed isolation and characterisation of the corresponding genes. Southern blot analysis of the cosmid clones and of uncloned genomic DNA has shown that there are single C2 and Factor B loci that are less than 500 bp apart. Molecular mapping has revealed that the C2 gene spans approximately 18 kb of DNA. This is in marked contrast to the Factor B gene which is 6 kb in length. The entire gene structure of the Factor B gene has been determined and the interesting features of this gene which have emerged from an examination of the intron-exon boundaries are discussed. C2 and Factor B are polymorphic and structural variants have been detected by differences in charge. The degree of polymorphism at the C2 and Factor B loci has been examined by Southern blot analysis of restriction digests of genomic DNA. Three DNA polymorphisms have been identified in the C2 gene. These polymorphisms subdivide the common allelic variant of C2 (C2C) and reveal that there is much greater variability at the C2 locus than that detected by protein typing. It is suggested that these DNA polymorphisms may serve as useful markers in the genetic analysis of diseases that are related to the major histocompatibility complex.

Amino Acid Sequence↗
PubMed2005

The significance of platelet-activating factor and fertility in the male primate: a review.

Since its discovery nearly 30 years ago platelet-activating factor (PAF) has emerged as one of the more important lipid mediators known. PAF (1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphorylcholine) exists endogenously as a mixture of molecular species with structural variants of the alkyl moiety. PAF is a novel potent signaling phospholipid that has unique pleiotropic biological properties in addition to platelet activation. PAF also plays a significant role in reproduction and is present in the sperm of a number of primate species. PAF content in squirrel monkey sperm is significantly higher during the breeding season than the non-breeding season. PAF content in rhesus sperm has a significant relationship with sperm motility. PAF content in human sperm has a positive correlation with seminal parameters and pregnancy outcomes. The enzymes (lyso-PAF-acetyltransferase and PAF-acetylhydrolase) necessary for PAF activation and deactivation are present in primate sperm. PAF-acetylhydrolase may act as a "decapacitation factor". Removal of this enzyme during capacitation promotes PAF synthesis increasing primate motility and fertilization. PAF also plays a significant role in the fertilization process, enhancing the fertilization rates of oocytes. Enhanced embryo development has also been reported in oocytes fertilized with PAF-treated sperm. Exogenous PAF will also significantly improve primate artificial insemination pregnancy outcomes. PAF antagonists inhibit sperm motility, acrosome reaction, and fertilization thus suggesting the presence of receptors for PAF. The PAF-receptor is present on primate sperm, with altered transcript levels and distribution patterns on abnormal cells. Whereas, the exact mechanism of PAF in sperm function and reproduction is uncertain, its importance in normal primate fertility is substantial.

Animals↗
PubMed1977

Linkage studies with C6.

The common structural variants of C6 have been used to study the linkage relations of the locus in human pedigrees. Linkage between C6 and RH, Fy, ACP1, MNSS, Jk, HLA, ABO, ESD, Hp, ADA, GPT, Gc, Pi, Gm and Km has been excluded at recombination fractions at least as great as 0-1 in the male.

Alleles↗