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Results for “Heterogeneity Mapping”

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PubMed2001

[Posttraumatic epilepsy: diagnosis and clinical variety].

125 patients with posttraumatic epilepsy (PTE) were examined using methods of neurovisualization (CT and MRI) and electroencephalography (EEG), including brain mapped EEG. The research resulted in the conclusion about heterogeneity of the disease. Differential diagnostic criteria were elaborated for three clinical variations of symptomatic epilepsy of the traumatic genesis. Besides, the second variation was a real PTE, with the most clear clinical signs. The knowledge about the ambiguous clinical pattern of the disease may improve therapy and prognosis, evaluate both physical and occupational abilities of the patients more objectively.

Adolescent↗

PubMed1988

Characterization of six partial deletions in the low-density-lipoprotein (LDL) receptor gene causing familial hypercholesterolemia (FH).

Two hundred thirty-four unrelated heterozygotes for familial hypercholesterolemia (FH) were screened to detect major rearrangements in the low-density-lipoprotein (LDL) receptor gene. Total genomic DNA was analyzed by Southern blot hybridization to probes encompassing exons 1-18 of the LDL receptor gene. Six different mutations were detected and characterized by the use of exon-specific probes and detailed restriction mapping. Each mutation is unique and suggests that molecular heterogeneity underlies the molecular pathology of FH. There appear to be preferential sites within the LDL receptor gene for major rearrangements resulting in deletions.

Chromosome Deletion↗

PubMed1997

Linkage analysis of Fanconi anaemia in Italy and mapping of the complementation group A gene.

Fanconi anaemia (FA) is an autosomal recessive disease characterised by genetic heterogeneity, with at least five complementation groups (FA-A to FA-E). The FAC gene has been cloned and localised to 9q22.3. The most frequent defective gene, FAA, was recently mapped to chromosome 16q24.3, in a region of 10 cM between D16S498 and the telomere. Eleven FA-A and 16 unclassified Italian families were analysed by microsatellite markers. To define the localisation of the FAA locus further, microsatellites were analysed at 16q24. All the families were consistent with linkage, the highest lod score being observed with D16S1320. Evidence for common haplotypes was obtained in two genetic isolates from the Brenta basin and the Naples region. Autozygosity mapping and haplotype analysis suggest that the FAA locus is distal to D16S305.

Cell Cycle Proteins↗

PubMed2006

Using endophenotypes for pathway clusters to map complex disease genes.

Nature determines the complexity of disease etiology and the likelihood of revealing disease genes. While culprit genes for many monogenic diseases have been successfully unraveled, efforts to map major complex disease genes have not been as productive as hoped. The conceptual framework currently adopted to deal with the heterogeneous nature of complex diseases focuses on using homogeneous internal features of the disease phenotype for mapping. However, phenotypic homogeneity does not equal genotypic homogeneity. In this report, we advocate working with well-measured phenotypes portrayed by amounts of transcripts and activities of gene products or their metabolites, which are pertinent to relatively small pathway clusters. Reliable and controlled measures for oligogenic traits resulting from proper dissection efforts may enhance statistical power. The large amounts of information obtained on gene and protein expression from technological advances can add to the power of gene finding, particularly for diseases with unclear etiology. Data-mining tools for dimension reduction can assist biologists to reveal novel molecular endophenotypes. However, there are still hurdles to overcome, including high cost, relatively poor reproducibility and comparability among platforms, the cross-sectional nature of the information, and the accessibility of human tissues. Concerted efforts are required to carry out large-scale prospective studies that are integrated at the levels of phenotype characterization, high throughput experimental techniques, data analyses, and beyond.

Chromosome Mapping↗

PubMed1990

Genetic homogeneity between acute and chronic forms of spinal muscular atrophy.

The childhood-onset spinal muscular atrophies (SMAs) describe a heterogeneous group of disorders that selectively affect the alpha motoneuron. We have shown that chronic childhood-onset SMA (SMA II and III) maps to a single locus on chromosome 5q. Acute SMA (SMA Type I/Werdnig-Hoffmann/severe/infantile) is the main cause of heritable infant mortality. Mapping the acute SMA locus by conventional methods is complicated by the rapidly fatal course of the disease and its recessive mode of inheritance. We present here the typing of four inbred acute-SMA families with DNA markers on chromosome 5q and analysis of these together with acute families from our previous study to demonstrate genetic homogeneity between the acute and chronic forms of SMA. The data indicate that the acute SMA locus maps to chromosome 5q11.2-13.3. Two families seem unlinked to 5q markers, raising the possibility of genetic heterogeneity or disease misclassification within the acute and chronic family sets.

Acute Disease↗

PubMed2005

Advanced microscopy solutions for monitoring the kinetics and dynamics of drug-DNA targeting in living cells.

Many anticancer drugs require interaction with DNA or chromatin components of tumor cells to achieve therapeutic activity. Quantification and exploration of drug targeting dynamics can be highly informative in the rational development of new therapies and in the drug discovery pipeline. The problems faced include the potential infrequency and transient nature of critical events, the influence of micropharmacokinetics on the drug-target equilibria, the dependence on preserving cell function to demonstrate dynamic processes in situ, the need to map events in functional cells and the confounding effects of cell-to-cell heterogeneity. We demonstrate technological solutions in which we have integrated two-photon laser scanning microscopy (TPLSM) to track drug delivery in subcellular compartments, with the mapping of sites of critical molecular interactions. We address key design concepts for the development of modular tools used to uncover the complexity of drug targeting in single cells. First, we describe the combination of two-photon excitation with fluorescence lifetime imaging microscopy (FLIM) to map the nuclear docking of the anticancer drug topotecan (TPT) at a subset of DNA sites in nuclear structures of live breast tumor cells. Secondly, we demonstrate how we incorporate the smart design of a two-photon 'dark' DNA binding probe, such as DRAQ5, as a well-defined quenching probe to uncover sites of drug interaction. Finally, we discuss the future perspectives on introducing these modular kinetic assays in the high-content screening arena and the interlinking of the consequences of drug-target interactions with cellular stress responses.

Antineoplastic Agents↗

PubMed1994

Progress in mapping human epilepsy genes.

The chromosomal loci for seven epilepsy genes have been identified in chromosomes 1q, 6p, 8q, 16p, 20q, 21q, and 22q. In 1987, the first epilepsy locus was mapped in a common benign idiopathic generalized epilepsy syndrome, juvenile myoclonic epilepsy (JME). Properdin factor or Bf, human leukocyte antigen (HLA), and DNA markers in the HLA-DQ region were genetically linked to JME and the locus, named EJM1, was assigned to the short arm of chromosome 6. Our latest studies, as well as those by Whitehouse et al., show that not all families with JME have their genetic locus in chromosome 6p, and that childhood absence epilepsy does not map to the same EJM1 locus. Recent results, therefore, favor genetic heterogeneity for JME and for the common idiopathic generalized epilepsies. Heterogeneity also exists in benign familial neonatal convulsions, a rare form of idiopathic generalized epilepsy. Two loci are now recognized; one in chromosome 20q (EBN1) and another in chromosome 8q. Heterogeneity also exists for the broad group of debilitating and often fatal progressive myoclonus epilepsies (PME). The gene locus (EPM1) for both the Baltic and Mediterranean types of PME or Unverricht-Lundborg disease is the same and is located in the long arm of chromosome 21. Lafora type of PME does not map to the same EPM1 locus in chromosome 21. PME can be caused by the juvenile type of Gaucher's disease, which maps to chromosome 1q, by the juvenile type of neuronal ceroid lipofuscinoses (CLN3), which maps to chromosome 16p, and by the "cherry-red-spot-myoclonus" syndrome of Guazzi or sialidosis type I, which has been localized to chromosome 10. A point mutation in the mitochondrial tRNA(Lys) coding gene can also cause PME in children and adults (MERFF).

Chromosome Mapping↗

PubMed1985

Immunocytochemical mapping of 1B236, a brain-specific neuronal polypeptide deduced from the sequence of a cloned mRNA.

The 318-amino acid, carboxy-terminal sequence of the putative brain-specific polypeptide 1B236 was deduced from the nucleotide sequence of its cloned brain-specific mRNA. Antisera raised against selected synthetic peptide fragments of this protein were used to map the cellular location of the presumptive gene product in the brains of normal or colchicine-pretreated adult rats. Antisera directed against any of three C-terminally located, but nonoverlapping, nonhomologous, synthetic peptide segments (P5, P6, or P7) produced virtually identical maps of intensely immunoreactive neuropil staining. The immunoreactivity was distributed heterogeneously and was most pronounced within olfactory, somatosensory, and limbic systems, and was more modest in certain motor and auditory structures. In colchicine-pretreated rats, large, multipolar perikarya were observed within the amygdala, caudate-putamen, cingulate, parietal, and piriform cortices, as well as in particular diencephalic and pontine nuclei. Smaller immunoreactive neurons with more limited dendritic extensions were observed in the olfactory bulb, the cerebellar cortex, and the dorsal horn and intermediolateral cell columns of the spinal cord. No immunoreactivity was observed in visceral structures innervated by the autonomic nervous system or in non-neural tissues. In addition to the virtually superimposable maps produced by antisera to all three synthetic fragments selected from the C-terminus of 1B236, some uniquely reactive sites were seen. Antisera to the most N-terminal of the three synthetic immunogens (P5) were reactive with neurons of the medial trapezoid nucleus and in nerve terminals surrounding the deep cerebellar nuclei. Antisera against the most C-terminal synthetic immunogen (P7) were reactive with neurons of the paraventricular and supraoptic hypothalamic nuclei. These data demonstrate that the 1B236 protein is located within selected neuronal elements within functionally related cellular circuits established more formally by other methods. Our data show that protein 1B236-immunoreactive cells share at least the expression of this protein and suggest that these cells may also be related epigenetically or evolutionarily. These data, together with other subcellular, ultrastructural, and electrophysiological properties of 1B236, suggest that this protein could be considered as a prohormone capable of yielding several final candidate transmitter products.

Animals↗

PubMed2002

Evidence of clinical and genetic heterogeneity in autosomal dominant congenital cerulean cataracts.

Autosomal dominant cerulean cataracts (ADCC) have previously been mapped to two loci: one on chromosome 17q24 and the other on chromosome 22q11.2-q12.2, which includes the beta-B2 crystallin (CRYBB2) candidate gene. Using polymorphic markers in these regions (D17S802, D17S836, D17S1806 and CRYBB2, D22S258) for linkage analysis, we excluded these loci in a large Moroccan family presenting with an unusual form of ADCC with early onset of lens opacities and rapid evolution. This finding confirms the clinical and genetic heterogeneity of autosomal dominant congenital cerulean cataracts.

Adult↗

PubMed1981

The 5' termini of RNAs encoded by the transposable element copia.

The 5' termini of copia-specific RNAs in Drosophila melanogaster tissue culture cells were determined by S1 nuclease mapping and cap analysis. Both major copia RNAs share an identical set of heterogeneous 5' ends. Three major cap 1 structures M7GpppCmpUp, M7GpppCmpCp and M7GpppGmpUp together with several other minor caps were found. Almost all the 5' termini, as judged by S-1 nuclease mapping, were located either in a pyrimidine-rich part of the terminal direct repeat or apparently outside of the copia element, suggesting that a proportion of copia transcripts derive from promoters external to the genetic element.

Animals↗

PubMed1995

Perspectives of identity by descent (IBD) mapping in founder populations.

In a founder population patients with a genetic disease are likely to share predisposing genes from a common ancestor. We show that, depending on the distance of the relationship, patients are expected to share extended segments of DNA around the disease gene. Because of the size of the shared segment, a genomic search with DNA markers for such shared segments, identity by descent (IBD) mapping, can efficiently find the map position of genes, particularly due to genetic drift leading to reduction of heterogeneity and the large number of meioses that is implicitly observed. The statistical power of this method and the approximate cost are given as a function of the density of the map of tested markers and the number of generations since a common ancestor. Initial marker spacings between 5 and 15 centiMorgans are shown to be optimal. IBD mapping is applicable to many genetic diseases, because it does not presuppose a specific genetic model.

Alleles↗

PubMed1996

World Wide Web-based access to heterogenous information resources for cytokine research and education.

Cytokines are currently the focus of intense research efforts, and information related to cytokine biology is expanding at an extremely rapid rate. The primary literature has become insufficient as a source for timely information, and efficient searches of the older literature are complicated by the nature of cytokine nomenclature. A few computer-accessible cytokine-related data sources have recently been developed, but these are typically limited in scope and not integrated with other information resources. We have developed Cytokine Explorer, a World Wide Web (WWW)-based resource to provide access to and guidance in use of information for research and education in cytokine biology. The resource consists of: (1) a searchable thesaurus of cytokine nomenclature; (2) a cytokine reagent database containing information from academic institutions and commercial sources; (3) a set of links to cytokine-related WWW sites; and (4) a database of functional information retrieval maps for guided retrieval of cytokine information from combinations of heterogeneous sources.

Computer Communication Networks↗

PubMed2004

Altered connexin43 expression produces arrhythmia substrate in heart failure.

Recently, we found that repolarization heterogeneities between subepicardial and midmyocardial cells can form a substrate for reentrant ventricular arrhythmias in failing myocardium. We hypothesized that the mechanism responsible for maintaining transmural action potential duration heterogeneities in heart failure is related to intercellular uncoupling from downregulation of cardiac gap junction protein connexin43 (Cx43). With the use of the canine model of pacing-induced heart failure, left ventricles were sectioned to expose the transmural surface (n = 5). To determine whether heterogeneous Cx43 expression influenced electrophysiological function, high-resolution transmural optical mapping of the arterially perfused canine wedge preparation was used to measure conduction velocity (theta(TM)), effective transmural space constant (lambda(TM)), and transmural gradients of action potential duration (APD). Absolute Cx43 expression in failing myocardium, quantified by confocal immunofluorescence, was uniformly reduced (by 40 +/- 3%, P < 0.01) compared with control. Relative Cx43 expression was heterogeneously distributed and lower (by 32 +/- 18%, P < 0.05) in the subepicardium compared with deeper layers. Reduced Cx43 expression in heart failure was associated with significant reductions in intercellular coupling between transmural muscle layers, as evidenced by reduced theta(TM) (by 18.9 +/- 4.9%) and lambda(TM) (by 17.2 +/- 1.4%; P < 0.01) compared with control. Heterogeneous transmural distribution of Cx43 in failing myocardium was associated with lower subepicardial theta(TM) (by 12 +/- 10%) and lambda(TM) (by 13 +/- 7%), compared with deeper transmural layers (P < 0.05). APD dispersion was greatest in failing myocardium, and the largest transmural APD gradients were consistently found in regions exhibiting lowest relative Cx43 expression. These data demonstrate that reduced Cx43 expression produces uncoupling between transmural muscle layers leading to slowed conduction and marked dispersion of repolarization between epicardial and deeper myocardial layers. Therefore, Cx43 expression patterns can potentially contribute to an arrhythmic substrate in failing myocardium.

Action Potentials↗

PubMed2001

Evidence for genetic heterogeneity in hereditary neuralgic amyotrophy.

Hereditary neuralgic amyotrophy (HNA) is a rare autosomal dominant disorder characterized by recurrent episodes of severe arm and shoulder pain with weakness, atrophy, and sensory impairment in a brachial plexus distribution. Recent studies mapped the HNA locus to chromosome 17q25. Two pedigrees with clinically typical HNA in which markers from chromosome 17q25 do not cosegregate with the disease and in which lod scores do not support linkage to chromosome 17q25 were identified.

Adult↗

PubMed1990

Heterogeneity among human T cell clones recognizing an HLA-DR4,Dw4-restricted epitope from the 18-kDa antigen of Mycobacterium leprae defined by synthetic peptides.

Synthetic peptides have been used to exactly define a T cell epitope region from the immunogenic 18-kDa protein of Mycobacterium leprae. Four M. leprae reactive CD4+ T cell clones, isolated from two healthy individuals vaccinated with killed M. leprae, recognized a determinant initially defined by the peptide (38-50). However, fine mapping of the minimal sequence required for T cell recognition revealed heterogeneity among the T cell clones with regard to the N- and carboxyl-terminal boundaries of the epitopes recognized. MHC restriction analysis showed that the immunogenic peptides were presented to the T cells in an HLA-DR4,Dw4-restricted manner in all cases. The results suggest that a polyclonal T cell response representing different fine specificities is directed toward a possible immunodominant epitope from the M. leprae 18-kDa Ag in individuals carrying this MHC haplotype.

Amino Acid Sequence↗

PubMed1998

A novel locus (RP24) for X-linked retinitis pigmentosa maps to Xq26-27.

Two genetic loci, RP2 and RP3, for X-linked retinitis pigmentosa (XLRP) have been localized to Xp11.3-11.23 and Xp21.1, respectively. RP3 appears to account for 70% of XLRP families; however, mutations in the RPGR gene (isolated from the RP3 region) are identified in only 20% of affected families. Close location of XLRP loci at Xp and a lack of unambiguous clinical criteria do not permit assignment of genetic subtype in a majority of XLRP families; nonetheless, in some pedigrees, both RP2 and RP3 could be excluded as the causative locus. We report the mapping of a novel locus, RP24, by haplotype and linkage analysis of a single XLRP pedigree. The RP24 locus was identified at Xq26-27 by genotyping 52 microsatellite markers spanning the entire X chromosome. A maximum LOD score of 4.21 was obtained with DXS8106. Haplotype analysis assigned RP24 within a 23-cM region between the DXS8094 (proximal) and DXS8043 (distal) markers. Other chromosomal regions and known XLRP loci were excluded by obligate recombination events between markers in those regions and the disease locus. Hemizygotes from the RP24 family have early onset of rod photoreceptor dysfunction; cone receptor function is normal at first, but there is progressive loss. Patients at advanced stages show little or no detectable rod or cone function and have clinical hallmarks of typical RP. Mapping of the RP24 locus expands our understanding of the genetic heterogeneity in XLRP and will assist in development of better tools for diagnosis.

Chromosome Mapping↗

PubMed2002

A new autosomal recessive non-progressive congenital cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities (CAMOS) maps to chromosome 15q24-q26 in a large consanguineous Lebanese Druze Family.

Congenital cerebellar ataxias are a heterogeneous group of non-progressive disorders characterized by hypotonia and developmental delay followed by the appearance of ataxia, and often associated with dysarthria, mental retardation, and atrophy of the cerebellum. We report the mapping of a disease gene in a large inbred Lebanese Druze family, with five cases of a new form of non-progressive autosomal recessive congenital ataxia associated with optic atrophy, severe mental retardation, and structural skin abnormalities, to a 3.6-cM interval on chromosome 15q24-15q26.

Abnormalities, Multiple↗

PubMed2000

Diagnostic findings from testis fine needle aspiration mapping in obstructed and nonobstructed azoospermic men.

PURPOSE: Although helpful for defining extratesticular obstruction, the testis biopsy offers limited information on nonobstructive azoospermic testes. Guided by diagnostic biopsies, testis sperm extraction procedures fail in 25% to 50% of patients with nonobstructive azoospermia, largely because it is clinically difficult to know where sperm are located. To provide a more complete assessment of spermatogenesis in nonobstructive azoospermic patients and to simplify the confirmation of sperm production in men with obstruction, we use a systematic, fine needle aspiration "mapping" procedure. We summarize the diagnostic findings in a series of azoospermic men. MATERIALS AND METHODS: From 118 azoospermic infertile men (22 with obstructed and 96 with nonobstructed azoospermia) fine needle aspiration data were used to generate location specific, sperm frequency maps for obstructed and nonobstructive azoospermic testes to determine if "sperm rich" locations existed. RESULTS: Fine needle aspiration map analysis revealed that all aspiration locations from obstructed cases showed sperm. In men with nonobstructive azoospermia, sperm was identified in the right testis in 134 of 652 (20.5%) and in the left testis in 151 of 716 (21.1%) separate aspirations. Rates of sperm detection among various intratesticular sites were not statistically different. In 27.1% of cases the fine needle aspiration map found sperm in men with sperm negative biopsies. The likelihood of heterogeneity in fine needle aspiration sperm findings was 25% within individual nonobstructive azoospermic testes and 19.2% between testis sides. At post-procedure followup of 88 patients (74%), no clinical or surgical complications were observed. CONCLUSIONS: Testis fine needle aspiration mapping is a simple, reliable and informative diagnostic tool in the evaluation of azoospermic infertile men.

Biopsy, Needle↗