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Triplet Repeat (triplet + repeat)
Selected AbstractsHypothalamic,endocrine aspects in Huntington's diseaseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2006Ĺsa Petersén Abstract Huntington's disease (HD) is a hereditary and fatal disorder caused by an expanded CAG triplet repeat in the HD gene, resulting in a mutant form of the protein huntingtin. Wild-type and mutant huntingtin are expressed in most tissues of the body but the normal function of huntingtin is not fully known. In HD, the neuropathology is characterized by intranuclear and cytoplasmic inclusions of huntingtin aggregates, and cell death primarily in striatum and cerebral cortex. However, hypothalamic atrophy occurs at early stages of HD with loss of orexin- and somatostatin-containing cell populations. Several symptoms of HD such as sleep disturbances, alterations in circadian rhythm, and weight loss may be due to hypothalamic dysfunction. Endocrine changes including increased cortisol levels, reduced testosterone levels and increased prevalence of diabetes are found in HD patients. In HD mice, alterations in the hypothalamic,pituitary,adrenal axis occurs as well as pancreatic ,-cell and adipocyte dysfunction. Increasing evidence points towards important pathology of the hypothalamus and the endocrine system in HD. As many neuroendocrine factors are secreted into the cerebrospinal fluid, blood and urine, it is possible that their levels may reflect the disease state in the central nervous system. Investigating neuroendocrine changes in HD opens up the possibility of finding biomarkers to evaluate future therapies for HD, as well as of identifying novel targets for therapeutic interventions. [source] Closely linked cis -acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes,HUMAN MUTATION, Issue 12 2007S. Ennis Abstract In its expanded form, the fragile X triplet repeat at Xq27.3 gives rise to the most common form of inherited mental retardation, fragile X syndrome. This high population frequency persists despite strong selective pressure against mutation-bearing chromosomes. Males carrying the full mutation rarely reproduce and females heterozygous for the premutation allele are at risk of premature ovarian failure. Our diagnostic facility and previous research have provided a large databank of X chromosomes that have been tested for the FRAXA allele. Using this resource, we have conducted a detailed genetic association study of the FRAXA region to determine any cis -acting factors that predispose to expansion of the CGG triplet repeat. We have genotyped SNP variants across a 650-kb tract centered on FRAXA in a sample of 877 expanded and normal X chromosomes. These chromosomes were selected to be representative of the haplotypic diversity encountered in our population. We found expansion status to be strongly associated with a ,50-kb region proximal to the fragile site. Subsequent detailed analyses of this region revealed no specific genetic determinants for the whole population. However, stratification of chromosomes by risk subgroups enabled us to identify a common SNP variant which cosegregates with the subset of D group haplotypes at highest risk of expansion (,=17.84, p=0.00002). We have verified that this SNP acts as a marker of repeat expansion in three independent samples. Hum Mutat 28(12), 1216,1224, 2007. © 2007 Wiley-Liss, Inc. [source] The increase in the frequency of MICA gene A6 allele in oral squamous cell carcinomaJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 6 2002Liu Chung-Ji Abstract Background: Oral squamous cell carcinoma (OSCC) was reported to be associated with immune function. The MICA (MHC class I chain-related gene A) is expressed by keratinocytes and other epithelial cells, and its encoded protein interacts with ,/, T cells localized in submucosa. The MICA also influences the heat shock protein function. We speculated that the alterations of MICA might influence the pathogenesis of OSCC through the aberration in presenting tumor antigens or heat shock protein. MICA gene has a triplet repeat (GCT) polymorphism in the transmembrane domain, resulting in five distinctive allelic patterns. Methods: We analysed this MICA polymorphism in 67 OSCC patients and 351 randomly selected unrelated controls. By using the ABI Prism 377,18 DNA sequencer (Applied Biosystems, Foster City, CA, USA) to analyse the sample DNA PCR products. The number of micro-satellite repeats was estimated with Genescan 672 software (Applied Biosystems) with a standard size marker of GS-350 TAMRA (N,N,N,N-tetramethyl-6-carbohydroxyl rhodamine; Applied Biosystems). Results: The phenotype frequency of allele A6 of MICA in subjects with OSCC was significantly higher than that in controls (RR = 3.46, 95% CI = 1.73,6.94, P = 0.0002), as was the frequency of allele (RR = 2.64, 95% CI = 1.39,5.02, P = 0.002). Conclusion: The results suggest that allele A6 in MICA might confer the risk of OSCC. [source] Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's diseaseMOVEMENT DISORDERS, Issue 4 2002Johannes Schiefer MD Abstract Glutamate excitotoxicity has been suggested to contribute to the pathogenesis of Huntington's disease (HD). Riluzole is a substance with glutamate antagonistic properties that is used for neuroprotective treatment in amyotrophic lateral sclerosis and which is currently tested in clinical trials for treatment of HD. R6/2 transgenic mice, which express exon 1 of the human HD gene with an expanded CAG triplet repeat, serve as a well-characterized mouse model for HD with progressing neurological abnormalities and limited survival. We treated R6/2 HD transgenic mice with riluzole orally beginning at a presymptomatic stage until death to investigate its potential neuroprotective effects in this mouse model and found that survival time in the riluzole group was significantly increased in comparison to placebo-treated transgenic controls. Additionally, the progressive weight loss was delayed and significantly reduced by riluzole treatment; behavioral testing of motor coordination and spontaneous locomotor activity, however, showed no statistically significant differences. We also examined the formation of the HD characteristic neuronal intranuclear inclusions (NII) immunohistologically. At a late disease stage, striatal NII from riluzole-treated transgenic mice showed profound changes in ubiquitination, i.e., NII were less ubiquitinated and surrounded by ubiquitinated micro-aggregates. Staining with antibodies directed against the mutated huntingtin revealed no significant difference in this component of NII. Taken together, these data suggest that riluzole is a promising candidate for neuroprotective treatment in human HD. © 2002 Movement Disorder Society [source] Novel genetic markers in the 5,-flanking region of ANKH are associated with ankylosing spondylitisARTHRITIS & RHEUMATISM, Issue 3 2003Florence W. L. Tsui Objective To use a candidate gene approach for the identification of genetic markers that are significantly linked to and associated with ankylosing spondylitis (AS). Methods We searched for novel polymorphisms in the ANKH gene (human homolog of the murine progressive ankylosis gene) and genotyped 2 polymorphic sites, one in the 5,-noncoding region and the other in the promoter region of ANKH, using DNA from affected (n = 273) and unaffected (n = 112) individuals from 124 AS families. We used these ANKH and other nearby polymorphisms to perform linkage and family-based association analyses. Results We identified 2 novel polymorphic sites: one in the 5,-noncoding region of ANKH involving 1,2 copies of an 8-bp repeat (denoted as ANKH-OR), and the other in the promoter region involving different copy numbers of a triplet repeat (denoted as ANKH-TR). ANKH-OR and ANKH-TR were in complete linkage disequilibrium. Five markers (D5S1953, ANKH-TR, ANKH-OR, D5S1954, and D5S1963) were used for both the linkage and association analyses. Multipoint linkage analysis of 124 AS families showed a modest level of significance (nonparametric linkage score 2.15; P = 0.015) at the ANKH region. The contribution of ANKH to AS susceptibility (,s) was 1.9. A family-based association study on the same AS families revealed that both ANKH-OR allele 1 and ANKH-TR allele 7 were significantly associated with disease, assuming an additive model (for ANKH-OR allele 1, P = 0.03; for ANKH-TR allele 7, P = 0.04). Conclusion Our results indicate that ANKH-OR and ANKH-TR are novel genetic markers that are significantly associated with AS. [source] Altered striatal amino acid neurotransmitter release monitored using microdialysis in R6/1 Huntington transgenic miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2001B. NicNiocaill Abstract Huntington's disease is an autosomal dominant disease which presents with striatal and cortical degeneration causing involuntary movements, dementia and emotional changes. We employed 16-week-old transgenic Huntington mice (R6/1 line developed by Bates and coworkers) that express exon 1 of the mutant human Huntington gene with 115 CAG triplet repeats. At this age, R6/1 mice do not exhibit an overt neurological phenotype nor any striatal neuronal loss. Using microdialysis, we monitored basal and intrastriatal N-methyl d -aspartate (NMDA, 100 µm, 15 min)- and KCl (100 mm, 15 min)-induced increases in local aspartate, glutamate and GABA release in halothane-anaesthetized transgenic mice and wild-type controls. Basal striatal dialysate glutamate levels were reduced by 42% in R6/1 mice whilst aspartate and GABA levels did not differ from those observed in control mice. Intrastriatal NMDA was associated with significantly greater aspartate (at 15 min) and GABA (at 30 min) levels in the R6/1 mice compared to controls, whilst glutamate release rapidly increased to the same extent in both groups. Intrastriatal KCl was associated with enhanced increases (30 min) in local aspartate and glutamate release in the R6/1 mice above those observed in controls whilst the rapid increase (15 min) in GABA release was similar in both groups. The results provide compelling evidence for specific alterations in both basal, as well as NMDA- and KCl-induced, release of striatal amino acid neurotransmitters in this transgenic model of Huntington's disease, even in the absence of manifest neurodegeneration. [source] In vitro expansion of DNA triplet repeats with bulge binders and different DNA polymerasesFEBS JOURNAL, Issue 18 2008Di Ouyang The expansion of DNA repeat sequences is associated with many genetic diseases in humans. Simple bulge DNA structures have been implicated as intermediates in DNA slippage within the DNA repeat regions. To probe the possible role of bulged structures in DNA slippage, we designed and synthesized a pair of simple chiral spirocyclic compounds [Xi Z, Ouyang D & Mu HT (2006) Bioorg Med Chem Lett16, 1180,1184], DDI-1A and DDI-1B, which mimic the molecular architecture of the enediyne antitumor antibiotic neocarzinostatin chromophore. Both compounds strongly stimulated slippage in various DNA repeats in vitro. Enhanced slippage synthesis was found to be synchronous for primer and template. CD spectra and UV thermal stability studies supported the idea that DDI-1A and DDI-1B exhibited selective binding to the DNA bulge and induced a significant conformational change in bulge DNA. The proposed mechanism for the observed in vitro expansion of long DNA is discussed. [source] Identification of Trinucleotide Repeat Ligands with a FRET Melting AssayCHEMBIOCHEM, Issue 8 2008Samir Amrane Dr. Abstract DNA hairpin structures formed within a repeated tract might be a causative factor for triplet expansion observed in several debilitating diseases. We have designed and used a fluorescence resonance energy transfer (FRET) melting assay to screen for ligands that bind specifically to the CNG triplet repeats. Using this assay, we screened a panel of 33 chemicals that were previously designed to bind DNA or RNA secondary structures. Remarkably, we found that macrocyclic compounds, such as acridine dimers and trimers, exhibit interesting affinities and specificities for this motif. [source] | ||||||||||||||||