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Several Candidate Genes (several + candidate_gene)
Selected AbstractsGene therapy in epilepsyEPILEPSIA, Issue 1 2009Véronique Riban Summary Results from animal models suggest gene therapy is a promising new approach for the treatment of epilepsy. Several candidate genes such as neuropeptide Y and galanin have been demonstrated in preclinical studies to have a positive effect on seizure activity. For a successful gene therapy-based treatment, efficient delivery of a transgene to target neurons is also essential. To this end, advances have been made in the areas of cell transplantation and in the development of recombinant viral vectors for gene delivery. Recombinant adeno-associated viral (rAAV) vectors in particular show promise for gene therapy of neurological disorders due to their neuronal tropism, lack of toxicity, and stable persistence in neurons, which results in robust, long-term expression of the transgene. rAAV vectors have been recently used in phase I clinical trials of Parkinson's disease with an excellent safety profile. Prior to commencement of phase I trials for gene therapy of epilepsy, further preclinical studies are ongoing including evaluation of the therapeutic benefit in chronic models of epileptogenesis, as well as assessment of safety in toxicological studies. [source] Molecular genetics of bipolar disorder and depressionPSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 1 2007TADAFUMI KATO md Abstract, In this review, all papers relevant to the molecular genetics of bipolar disorder published from 2004 to the present (mid 2006) are reviewed, and major results on depression are summarized. Several candidate genes for schizophrenia may also be associated with bipolar disorder: G72, DISC1, NRG1, RGS4, NCAM1, DAO, GRM3, GRM4, GRIN2B, MLC1, SYNGR1, and SLC12A6. Of these, association with G72 may be most robust. However, G72 haplotypes and polymorphisms associated with bipolar disorder are not consistent with each other. The positional candidate approach showed an association between bipolar disorder and TRPM2 (21q22.3), GPR50 (Xq28), Citron (12q24), CHMP1.5 (18p11.2), GCHI (14q22-24), MLC1 (22q13), GABRA5 (15q11-q13), BCR (22q11), CUX2, FLJ32356 (12q23-q24), and NAPG (18p11). Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation. From gene expression analysis, PDLIM5, somatostatin, and the mtDNA 3243 mutation were found to be related to bipolar disorder. Whereas most previous positive findings were not supported by subsequent studies, DRD1 and IMPA2 have been implicated in follow-up studies. Several candidate genes in the circadian rhythm pathway, BmaL1, TIMELESS, and PERIOD3, are reported to be associated with bipolar disorder. Linkage studies show many new linkage loci. In depression, the previously reported positive finding of a gene,environmental interaction between HTTLPR (insertion/deletion polymorphism in the promoter of a serotonin transporter) and stress was not replicated. Although the role of the TPH2 mutation in depression had drawn attention previously, this has not been replicated either. Pharmacogenetic studies show a relationship between antidepressant response and HTR2A or FKBP5. New technologies for comprehensive genomic analysis have already been applied. HTTLPR and BDNF promoter polymorphisms are now found to be more complex than previously thought, and previous papers on these polymorphisms should be treated with caution. Finally, this report addresses some possible causes for the lack of replication in this field. [source] A genome wide association study for QTL affecting direct and maternal effects of stillbirth and dystocia in cattleANIMAL GENETICS, Issue 3 2010H. G. Olsen Summary Dystocia and stillbirth are significant causes of female and neonatal death in many species and there is evidence for a genetic component to both traits. Identifying causal mutations affecting these traits through genome wide association studies could reveal the genetic pathways involved and will be a step towards targeted interventions. Norwegian Red cattle are an ideal model breed for such studies as very large numbers of records are available. We conducted a genome wide association study for direct and maternal effects of dystocia and stillbirth using almost 1 million records of these traits. Genotyping costs were minimized by genotyping the sires of the recorded cows, and using daughter averages as phenotypes. A dense marker map containing 17 343 single nucleotide polymorphisms covering all autosomal chromosomes was utilized. The genotyped sires were assigned to one of two groups in an attempt to ensure independence between the groups. Associations were only considered validated if they occurred in both groups. Strong associations were found and validated on chromosomes 4, 5, 6, 9, 12, 20, 22 and 28. The QTL region on chromosome 6 was refined using LDLA analysis. The results showed that this chromosome most probably contains two QTL for direct effect on dystocia and one for direct effect on stillbirth. Several candidate genes may be identified close to these QTL. Of these, a cluster of genes expected to affect bone and cartilage formation (i.e. SPP1, IBSP and MEPE) are of particular interest and we suggest that these genes are screened in candidate gene studies for dystocia and stillbirth in cattle as well as other species. [source] Genetic basis of rett syndromeDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2002Ignatia B. Van den Veyver Abstract The origin of Rett syndrome has long been debated, but several observations have suggested an X-linked dominant inheritance pattern. We and others have pursued an exclusion-mapping strategy using DNA from a small number of familial Rett syndrome cases. This work resulted in the narrowing of the region likely to harbor the mutated gene to Xq27.3-Xqter. After systematic exclusion of several candidate genes, we discovered mutations in MECP2, the gene that encodes the transcriptional repressor, methyl-CpG-binding protein 2. Since then, nonsense, missense, or frameshift mutations have been found in at least 80% of girls affected with classic Rett syndrome. Sixty-four percent of mutations are recurrent C > T transitions at eight CpG dinucleotides mutation hotspots, while the C-terminal region of the gene is prone to recurrent multinucleotide deletions (11%). Most mutations are predicted to result in total or partial loss of function of MeCP2. There is no clear correlation between the type and position of the mutation and the phenotypic features of classic and variant Rett syndrome patients, and XCI appears to be a major determinant of phenotypic severity. Further research focuses on the pathogenic consequences of these mutations along the hypothesis of loss of transcriptional repression of a small number of genes that are essential for neuronal function in the maturing brain. MRDD Research Reviews 2002;8:82,86. © 2002 Wiley-Liss, Inc. [source] Small-conductance Cl, channels contribute to volume regulation and phagocytosis in microgliaEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2007Guillaume Ducharme Abstract The shape and volume of microglia (brain immune cells) change when they activate during brain inflammation and become migratory and phagocytic. Swollen rat microglia express a large Cl, current (IClswell), whose biophysical properties and functional roles are poorly understood and whose molecular identity is unknown. We constructed a fingerprint of useful biophysical properties for comparison with IClswell in other cell types and with cloned Cl, channels. The microglial IClswell was rapidly activated by cell swelling but not by voltage, and showed no time-dependence during voltage-clamp steps. Like IClswell in many cell types, the halide selectivity sequence was I, > Br, > Cl, > F,. However, it differed in lacking inactivation, even at +100 mV with high extracellular Mg2+, and in having a much lower single-channel conductance: 1,3 pS. Based on these fundamental differences, the microglia channel is apparently a different gene product than the more common intermediate-conductance IClswell. Microglia express several candidate genes, with relative mRNA expression levels of: CLIC1 > ClC3 > ICln , ClC2 > Best2 > Best1 , Best3 > Best4. Using a pharmacological toolbox, we show that all drugs that reduced the microglia current (NPPB, IAA-94, flufenamic acid and DIOA) increased the resting cell volume in isotonic solution and inhibited the regulatory volume decrease that followed cell swelling in hypotonic solution. Both channel blockers tested (NPPB and flufenamic acid) dose-dependently inhibited microglia phagocytosis of E. coli bacteria. Because IClswell is involved in microglia functions that involve shape and volume changes, it is potentially important for controlling their ability to migrate to damage sites and phagocytose dead cells and debris. [source] Individual vulnerability to escalated aggressive behavior by a low dose of alcohol: decreased serotonin receptor mRNA in the prefrontal cortex of male miceGENES, BRAIN AND BEHAVIOR, Issue 1 2010S. Chiavegatto Low to moderate doses of alcohol consumption induce heightened aggressive behavior in some, but not all individuals. Individual vulnerability for this nonadaptive behavior may be determined by an interaction of genetic and environmental factors with the sensitivity of alcohol's effects on brain and behavior. We used a previously established protocol for alcohol oral self-administration and characterized alcohol-heightened aggressive (AHA) mice as compared with alcohol non-heightened (ANA) counterparts. A week later, we quantified mRNA steady state levels of several candidate genes in the serotonin [5-hydroxytryptamine (5-HT)] system in different brain areas. We report a regionally selective and significant reduction of all 5-HT receptor subtype transcripts, except for 5-HT3, in the prefrontal cortex of AHA mice. Comparable gene expression profile was previously observed in aggressive mice induced by social isolation or by an anabolic androgenic steroid. Additional change in the 5-HT1B receptor transcripts was seen in the amygdala and hypothalamus of AHA mice. In both these areas, 5-HT1B mRNA was elevated when compared with ANA mice. In the hypothalamus, AHA mice also showed increased transcripts for 5-HT2A receptor. In the midbrain, 5-HT synthetic enzyme, 5-HT transporter and 5-HT receptors mRNA levels were similar between groups. Our results emphasize a role for postsynaptic over presynaptic 5-HT receptors in mice which showed escalated aggression after the consumption of a moderate dose of alcohol. This gene expression profile of 5-HT neurotransmission components in the brain of mice may suggest a vulnerability trait for alcohol-heightened aggression. [source] Genetic influences on human brain structure: A review of brain imaging studies in twins,HUMAN BRAIN MAPPING, Issue 6 2007Jiska S. Peper Abstract Twin studies suggest that variation in human brain volume is genetically influenced. The genes involved in human brain volume variation are still largely unknown, but several candidate genes have been suggested. An overview of structural Magnetic Resonance (brain) Imaging studies in twins is presented, which focuses on the influence of genetic factors on variation in healthy human brain volume. Twin studies have shown that genetic effects varied regionally within the brain, with high heritabilities of frontal lobe volumes (90,95%), moderate estimates in the hippocampus (40,69%), and environmental factors influencing several medial brain areas. High heritability estimates of brain structures were revealed for regional amounts of gray matter (density) in medial frontal cortex, Heschl's gyrus, and postcentral gyrus. In addition, moderate to high heritabilities for densities of Broca's area, anterior cingulate, hippocampus, amygdala, gray matter of the parahippocampal gyrus, and white matter of the superior occipitofrontal fasciculus were reported. The high heritability for (global) brain volumes, including the intracranium, total brain, cerebral gray, and white matter, seems to be present throughout life. Estimates of genetic and environmental influences on age-related changes in brain structure in children and adults await further longitudinal twin-studies. For prefrontal cortex volume, white matter, and hippocampus volumes, a number of candidate genes have been identified, whereas for other brain areas, only a few or even a single candidate gene has been found so far. New techniques such as genome-wide scans may become helpful in the search for genes that are involved in the regulation of human brain volume throughout life. Hum Brain Mapp, 2007. © 2007 Wiley-Liss, Inc. [source] Identification of genes influencing skeletal phenotypes in congenic P/NP ratsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2010Imranul Alam Abstract We previously showed that alcohol-preferring (P) rats have higher bone density than alcohol-nonpreferring (NP) rats. Genetic mapping in P and NP rats identified a major quantitative trait locus (QTL) between 4q22 and 4q34 for alcohol preference. At the same location, several QTLs linked to bone density and structure were detected in Fischer 344 (F344) and Lewis (LEW) rats, suggesting that bone mass and strength genes might cosegregate with genes that regulate alcohol preference. The aim of this study was to identify the genes segregating for skeletal phenotypes in congenic P and NP rats. Transfer of the NP chromosome 4 QTL into the P background (P.NP) significantly decreased areal bone mineral density (aBMD) and volumetric bone mineral density (vBMD) at several skeletal sites, whereas transfer of the P chromosome 4 QTL into the NP background (NP.P) significantly increased bone mineral content (BMC) and aBMD in the same skeletal sites. Microarray analysis from the femurs using Affymetrix Rat Genome arrays revealed 53 genes that were differentially expressed among the rat strains with a false discovery rate (FDR) of less than 10%. Nine candidate genes were found to be strongly correlated (r2,>,0.50) with bone mass at multiple skeletal sites. The top three candidate genes, neuropeptide Y (Npy), , synuclein (Snca), and sepiapterin reductase (Spr), were confirmed using real-time quantitative PCR (qPCR). Ingenuity pathway analysis revealed relationships among the candidate genes related to bone metabolism involving ,-estradiol, interferon-,, and a voltage-gated calcium channel. We identified several candidate genes, including some novel genes on chromosome 4 segregating for skeletal phenotypes in reciprocal congenic P and NP rats. © 2010 American Society for Bone and Mineral Research [source] Localization of the Gene Causing the Osteopetrotic Phenotype in the Incisors Absent (Ia) Rat on Chromosome 10q32.1,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2004Liesbeth van Wesenbeeck Abstract The incisors absent rat is an osteopetrotic animal model. Segregation analysis in 37 affected animals from an outcross enabled us to assign the disease causing gene to a 4.7-cM interval on rat chromosome 10q32.1. Further analysis of the genes mapped in this region will provide more insight into the underlying pathogenesis. Introduction: Many of the insights into the factors that regulate the differentiation and activation of osteoclasts are gained from different spontaneous and genetically induced osteopetrotic animal models. The osteopetrotic incisors absent (ia) rat exhibits a generalized skeletal sclerosis and a delay of tooth eruption. Although the ia rat has well been studied phenotypically, the genetic defect still remains unknown. Material and Methods: To map the ia locus, we outcrossed the inbred ia strain with the inbred strain Brown Norway. Intercrossing F1 animals produced the F2 generation. Thirty-one mutant F2 animals and six mutant F4 animals were available for segregation analysis. Results: Segregation analysis enabled us to assign the disease causing gene to rat chromosome 10q32.1. Homozygosity for the ia allele was obtained for two of the markers analyzed (D10Rat18 and D10Rat84). Key recombinations delineate a candidate region of 4.7 cM flanked by the markers D10Rat99 and D10Rat17. Conclusion: We have delineated a 4.7-cM region on rat chromosome 10q32.1 in which the gene responsible for the osteopetrotic phenotype of the ia rat is located. Although the sequence of this chromosomal region is not complete, over 140 known or putative genes have already been assigned to this region. Among these, several candidate genes with a putative role in osteoclast functioning can be identified. However, at this point, it cannot be excluded that one of the genes with a currently unknown function is involved in the pathogenesis of the ia rat. Further analysis of the genes mapped in this region will provide us more insight into the pathogenesis of this osteopetrotic animal model. [source] An integrated analysis of the genome of the hyperthermophilic archaeon Pyrococcus abyssiMOLECULAR MICROBIOLOGY, Issue 6 2003Georges N. Cohen Summary The hyperthermophilic euryarchaeon Pyrococcus abyssi and the related species Pyrococcus furiosus and Pyrococcus horikoshii, whose genomes have been completely sequenced, are presently used as model organisms in different laboratories to study archaeal DNA replication and gene expression and to develop genetic tools for hyperthermophiles. We have performed an extensive re-annotation of the genome of P. abyssi to obtain an integrated view of its phylogeny, molecular biology and physiology. Many new functions are predicted for both informational and operational proteins. Moreover, several candidate genes have been identified that might encode missing links in key metabolic pathways, some of which have unique biochemical features. The great majority of Pyrococcus proteins are typical archaeal proteins and their phylogenetic pattern agrees with its position near the root of the archaeal tree. However, proteins probably from bacterial origin, including some from mesophilic bacteria, are also present in the P. abyssi genome. [source] Genome-wide analysis of DNA copy number alterations and gene expression in gastric cancer,THE JOURNAL OF PATHOLOGY, Issue 4 2008Y Tsukamoto Abstract Genomic copy number aberrations (CNAs) are believed to play a major role in the development and progression of human cancers. Although many CNAs have been reported in gastric cancer, their genome-wide transcriptional consequences are poorly understood. In this study, to reveal the impact of CNAs on genome-wide expression in gastric cancer, we analysed 30 cases of gastric cancers for their CNAs by array comparative genomic hybridization (array CGH) and 24 of these 30 cases for their expression profiles by oligonucleotide-expression microarray. We found that with the application of laser microdissection, most CNAs were detected at higher frequency than in previous studies. Notably, gain at 20q13 was detected in almost all cases (97%), suggesting that this may play an important role in the pathogenesis of gastric cancer. By comparing the array CGH data with expression profiles of the same samples, we showed that both genomic amplification and deletion strongly influence the expression of genes in altered genomic regions. Furthermore, we identified 125 candidate genes, consisting of 114 up-regulated genes located in recurrent regions (>10%) of amplification and 11 down-regulated genes located in recurrent regions of deletion. Up-regulation of several candidate genes, such as CDC6, SEC61G, ANP32E, BYSL and FDFT1, was confirmed by immunohistochemistry. Interestingly, some candidate genes were localized at genomic loci adjacent to well-known genes such as EGFR, ERBB2 and SMAD4, and concordantly deregulated by genomic alterations. Based on these results, we propose that our list of candidate genes may contain novel genes involved in the pathogenesis of advanced gastric cancer. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Characterization of a QTL region affecting clinical mastitis and protein yield on BTA6ANIMAL GENETICS, Issue 5 2009H. Nilsen Summary Quantitative trait loci affecting clinical mastitis were detected and fine mapped to a narrow region on bovine chromosome 6 in the Norwegian Red cattle population. The region includes the casein gene cluster and several candidate genes thought to influence clinical mastitis. The most significant results were found for SNPs within the Mucin 7 gene. This gene encodes an antimicrobial peptide and constitutes part of the first line of defence for the mucosal immune system. Detection of long haplotypes extending several Mb may indicate that artificial selection has influenced the haplotype structures in the region. A search for selection sweeps supports this observation and coincides with association results found both by single SNP and haplotype analyses. Our analyses identified haplotypes carrying quantitative trait loci alleles associated with high protein yield and simultaneously fewer incidences of clinical mastitis. The fact that such haplotypes are found in relative high frequencies in Norwegian Red may reflect the combined breeding goal that is characterized by selection for both milk production and disease resistance. The identification of these haplotypes raises the possibility of overcoming the unfavourable genetic correlation between these traits through haplotype-assisted selection. [source] Mutation screening of interferon regulatory factor 1 gene (IRF-1) as a candidate gene for atopy/asthmaCLINICAL & EXPERIMENTAL ALLERGY, Issue 11 2000E. Noguchi Background IL-4 gene cluster on chromosome 5 contains several candidate genes for atopy and asthma. Several independent studies have shown evidence for linkage between the markers flanking IL-4 gene cluster and asthma and/or asthma-related traits. Interferon regulatory factor 1 (IRF-1) is located approximately 300 kb telomeric to IL-4 and recent study reveals that IRF-1 deficiency results in an elevated production of Th2-related cytokines and a compensatory decrease in the expression of native cell- and Th1-related cytokines. Objective To determine if there are any mutations associated with the development of atopy and asthma present in the coding exons and 5, flanking region of the IRF-1 gene. Methods and results We have screened the promoter and coding regions of the IRF-1 gene in atopic asthmatics and controls by SSCP method. We found three novel nuclear variants (the ,300G/T and 4396 A/G polymorphisms and the 6355G > A rare variant) in the IRF-1 gene. No variants causing amino acid alterations of IRF-1 were detected. The ,300G/T polymorphism was in nearly complete linkage disequilibrium with the 4396 A/G polymorphism. An association between the 4396 A > G polymorphism and atopy/asthma was examined by transmission disequilibrium test in 81 asthmatic families. Either of 4396 A or 4396G alleles was not significantly preferentially transmitted to atopy- or asthma-affected children. Conclusion The IRF-1 gene is less likely to play a substantial role in the development of atopy and asthma in the Japanese population. [source] | |||||||||||||