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At least 271 records · Page 15Linked to original sources
PubMed2004

Genetic and phenotypic variation of West Nile virus in New York, 2000-2003.

West Nile virus (WNV) strains circulating during the first five years of WNV transmission in New York were collected, partial nucleotide sequences were determined, and in vitro and in vivo phenotypic analyses of selected strains were undertaken to determine whether observed increases in the intensity of enzootic and epidemic transmission in New York State during 2002 and 2003 were associated with viral genetic changes. Functionally diverse regions of the WNV genome were also compared to determine whether some regions may be more or less variable than others. The complete envelope coding regions of 67 strains and fragments of the nonstructural protein 5 (NS5) and 3' noncoding regions of 39 strains collected during 2002 and 2003 were examined. West Nile virus in New York remains relatively genetically homogeneous. Viral genetic diversity was greater in 2002 and 2003 at both the nucleotide and amino acid levels than in previous years due to the emergence of a new WNV genotype in 2002. This genotype persisted and became dominant in 2003. Envelope and NS5 coding regions were approximately two-fold more likely than the 3' untranslated region to contain nucleotide substitutions, and the envelope region was approximately three-fold more likely to contain amino acid substitutions than the NS5 region. Variation was noted in in vivo mosquito transmission assays, but not in in vitro growth studies. Strains belonging to the epizootiologically dominant clade were transmitted after approximately two fewer days of extrinsic incubation, providing a possible mechanism for the dominance of this clade. The observed increase in the intensity of WNV transmission beginning in 2002 was associated with an increase in viral genetic diversity that was the result of the emergence of an additional phylogenetic clade. This genotype seems to possess an advantage over previously recognized WNV strains in mosquito transmission phenotype.

Aedes↗
PubMed2003

Alterations of BLU, a candidate tumor suppressor gene on chromosome 3p21.3, in human nasopharyngeal carcinoma.

Nonrandom allelic loss on chromosome 3p is a common event in nasopharyngeal carcinoma (NPC) with the implication that certain tumor suppressor gene(s) in this region are involved in the pathogenesis of these tumors. The BLU gene, located at 3p21.3, has recently been identified as a candidate tumor suppressor gene due to the occurrence of missense mutations and loss of its expression in lung cancer. To investigate the involvement of BLU gene in NPC, we examined both genetic and epigenetic changes of BLU in NPC primary tumors and cell lines. No pathogenic mutations were detected in the entire coding region of this gene in 45 primary NPC tumors and 5 NPC cell lines. While BLU was expressed in 100% (15 of 15) of noncancerous nasopharyngeal epithelia, its transcripts were missing in all 5 NPC cell lines, and absent or reduced mRNA levels were observed in 78% (28 of 36) of the primary tumors. In the NPC cell lines, loss of BLU expression correlated with hypermethylation of the CpG island promoter sequence, and expression was restored after treatment with 5'-aza-2'-deoxycytidine. Methylation specific PCR analysis revealed that the BLU promoter was highly methylated in 74% (17 of 23) of primary tumors in which BLU was downregulated, whereas only 2 of 9 non-neoplastic nasopharyngeal epithelia exhibited hypermethylation in the BLU promoter region. The high incidence of BLU alterations suggests that it may be one of the critical tumor suppressor genes on chromosome 3p21.3 involved in the development of NPC.

Adult↗
PubMed2003

Likelihood models of somatic mutation and codon substitution in cancer genes.

The role of somatic mutation in cancer is well established and several genes have been identified that are frequent targets. This has enabled large-scale screening studies of the spectrum of somatic mutations in cancers of particular organs. Cancer gene mutation databases compile the results of many studies and can provide insight into the importance of specific amino acid sequences and functional domains in cancer, as well as elucidate aspects of the mutation process. Past studies of the spectrum of cancer mutations (in particular genes) have examined overall frequencies of mutation (at specific nucleotides) and of missense, nonsense, and silent substitution (at specific codons) both in the sequence as a whole and in a specific functional domain. Existing methods ignore features of the genetic code that allow some codons to mutate to missense, or stop, codons more readily than others (i.e., by one nucleotide change, vs. two or three). A new codon-based method to estimate the relative rate of substitution (fixation of a somatic mutation in a cancer cell lineage) of nonsense vs. missense mutations in different functional domains and in different tumor tissues is presented. Models that account for several potential influences on rates of somatic mutation and substitution in cancer progenitor cells and allow biases of mutation rates for particular dinucleotide sequences (CGs and dipyrimidines), transition vs. transversion bias, and variable rates of silent substitution across functional domains (useful in detecting investigator sampling bias) are considered. Likelihood-ratio tests are used to choose among models, using cancer gene mutation data. The method is applied to analyze published data on the spectrum of p53 mutations in cancers. A novel finding is that the ratio of the probability of nonsense to missense substitution is much lower in the DNA-binding and transactivation domains (ratios near 1) than in structural domains such as the linker, tetramerization (oligomerization), and proline-rich domains (ratios exceeding 100 in some tissues), implying that the specific amino acid sequence may be less critical in structural domains (e.g., amino acid changes less often lead to cancer). The transition vs. transversion bias and effect of CpG dinucleotides on mutation rates in p53 varied greatly across cancers of different organs, likely reflecting effects of different endogenous and exogenous factors influencing mutation in specific organs.

Data Interpretation, Statistical↗
PubMed2005

Characterization of the in vitro transcriptional activity of polymorphic alleles of the human monoamine oxidase-B gene.

The activity of monoamine oxidase-B (MAO-B) enzyme has a high degree of heritability, although no common genetic polymorphisms are present in the MAO-B coding region. The only known polymorphisms in MAO-B gene are a C-1,114T in the 5' region, a variable number of GT repeats in intron 2, and a G/A change in intron 13. The genetically determined differences in MAO-B activity among subjects most likely derive from functional differences conferred by these three MAO-B genetic polymorphisms, or by polymorphisms in trans-acting factors that regulate MAO-B expression. In order to identify differences in transcriptional activity conferred by the MAO-B genetic variants, we cloned alternative alleles at the three polymorphic loci in -1,114, intron 2 and intron 13, and tested them in transfection-luciferase assays in HepG2 hepatoma and 1321N1 astrocytoma cells. The mutant -1,114 allele T had higher activity than allele C in both cell lines, when cloned in pGL3Enhancer. Significant differences in trascriptional activity by intron 2 GT repeat allele were also observed, and varied by cell type and reporter construct. Allele G of intron 13 had significantly higher activity than allele A in both cell lines. These results indicate transcriptional activity differences between MAO-B variant alleles that are naturally occurring in the population.

Alleles↗
PubMed2003

Genetic material in the early evolution of bacteria.

DNA and RNA are nucleic acids that cells and viruses use to produce copies of themselves. However, there is an immense paucity of knowledge on how these nucleic acids originated and changed as early bacteria became capable of growth and cell division. One possibility is that parallel evolution of the genetic code and protein synthesis was required for assembly of the first cells capable of growth and division. It is also possible that DNA-RNA duplices were intermediate genetic material in the early assembly of the first cells. These ideas will be discussed as well as other aspects of the assembly of the first cells on the Earth.

Bacteria↗
PubMed2003

Decreased function of genetic variants, Pro283Leu and Arg287Gly, in human organic cation transporter hOCT1.

We have evaluated the functional consequences of genetic variations in human organic cation transporter hOCT1 (SLC22A1). Three coding single nucleotide polymorphisms (cSNPs) resulted in the amino acid changes Pro283Leu, Arg287Gly and Pro341Leu were assessed. Uptake experiments with transient expression system using HEK293 cells revealed that the variants Pro283Leu and Arg287Gly had completely diminished transport activity. The other variant Pro341Leu had a significantly, but not completely, decreased transport activity. Western blot analysis showed that the expression levels of all three variant proteins in the crude membranes of HEK293 cells were comparable to those of wild type hOCT1. Moreover, the expression of variant proteins at the plasma membrane was confirmed by indirect immunofluorescence, indicating that these SNPs did not affect the membrane localization of hOCT1. Present results suggest that the amino acid residues Pro283 and Arg287 have a substantial role in substrate recognition of hOCT1.

Journal Article↗
PubMed1999

From genotype to phenotype: a clinical pathological, and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused by the P301L tau mutation.

Frontotemporal dementia is a heterogeneous, often inherited disorder that typically presents with the insidious onset of behavioral and personality changes. Two genetic loci have been identified and mutations in tau have been causally implicated in a subset of families linked to one of these loci on chromosome 17q21-22. In this study, linkage analysis was performed in a large pedigree, the MN family, suggesting chromosome 17q21-22 linkage. Mutational analysis of the tau coding region identified a C-to-T change in exon 10 that resulted in the conversion of proline to a leucine (P301L) that segregated with frontotemporal dementia in this family. The clinical and pathological findings in the MN family emphasize the significant overlap between Pick's disease, corticobasal degeneration, and frontotemporal dementia and challenge some of the current dogma surrounding this condition. Pathological studies of two brains from affected members of Family MN obtained at autopsy demonstrate numerous tau-positive inclusions that were most prominent in the frontal lobes, anterior temporal lobes, and brainstem structures, as well as Pick-like bodies and associated granulovacuolar degeneration. These Pick-like bodies were observed in 1 patient with motor neuron disease. Because exon 10 is present only in tau mRNA coding for a protein with four microtubule binding repeats (4R), this mutation should selectively affect 4Rtau isoforms. Indeed, immunoblotting demonstrated that insoluble 4Rtau is selectively aggregated in both gray and white matter of affected individuals. Although there was significant pathological similarity between the 2 cases, the pattern of degenerative changes and tau-positive inclusions was not identical, suggesting that other genetic or epigenetic factors can significantly modify the regional topology of neurodegeneration in this condition.

Brain↗
PubMed2004

Postmortem molecular screening in unexplained sudden death.

OBJECTIVES: We examined the prevalence of defects in arrhythmia-related candidate genes among patients with unexplained sudden cardiac death (SCD). BACKGROUND: Patients with unexplained sudden death may constitute up to 5% of overall SCD cases. For such patients, systematic postmortem genetic analysis of archived tissue, using a candidate gene approach, may identify etiologies of SCD. METHODS: We performed analysis of KCNQ1 (KVLQT1), KCNH2 (HERG), SCN5A, KCNE1, and KCNE2 defects in a subgroup of 12 adult subjects with unexplained sudden death, derived from a 13-year, 270-patient autopsy series of SCD. Archived, paraffin-embedded myocardial tissue blocks obtained at the original postmortem examination were the source of deoxyribonucleic acid for genetic analysis. RESULTS: Two patients were found to have the same HERG defect, a missense mutation in exon 7 (nucleotide change G1681A, coding effect A561T). The mutation was heterozygous in Patient 1, but Patient 2 appeared to be homozygous for the defect. Patch-clamp recordings showed that the A561T mutant channel expressed in human embryonic kidney cells failed to generate HERG current. Western blot analysis implicated a trafficking defect in the protein, resulting in loss of post-translational processing from the immature to the mature form of HERG. No mutations were detected among the remaining four candidate genes. CONCLUSIONS: In this autopsy series, only 2 of 12 patients with unexplained sudden death were observed to have a defect in HERG among five candidate genes tested. It is likely that elucidation of SCD mechanisms in such patients will await the discovery of multiple, novel arrhythmia-causing gene defects.

Adult↗
PubMed2004

Novel mutation in the SPG3A gene in an African American family with an early onset of hereditary spastic paraplegia.

BACKGROUND: Mutations in a novel GTPase gene SPG3A cause an autosomal dominant hereditary spastic paraplegia linked to chromosome 14q (SPG3), which accounts for approximately 10% to 15% of all autosomal dominant hereditary spastic paraplegia cases. The mutational spectrum of the SPG3A gene and the phenotype/genotype correlations have not yet been established. OBJECTIVE: To describe a kindred with an infantile onset of hereditary spastic paraplegia caused by a novel mutation in the SPG3A gene. PATIENTS: Complete neurological examination and genetic analysis were performed on 6 affected members of a small African American kindred. Linkage analysis to genetic markers near autosomal dominant hereditary spastic paraplegia loci on chromosomes 2p and 14q was performed. The coding sequence of the SPG3A gene was analyzed, and the identified change in the sequence was tested for being a benign polymorphism by sequencing 200 chromosomes from normal controls. RESULTS: Every affected individual had signs of uncomplicated spastic paraparesis without additional neurological abnormalities. None of the affected family members had ever walked normally. The history was consistent with an infantile onset, despite the normal acquisition of motor milestones. Genetic analysis suggested linkage to the SPG3A locus on chromosome 14q. Analysis of the SPG3A gene revealed a missense mutation C635T, predicted to result in a threonine to isoleucine substitution at codon 156. Analysis of 200 normal chromosomes did not identify the same change in healthy subjects. CONCLUSION: We report a novel mutation in the SPG3A gene in an African American family with an infantile onset of autosomal dominant hereditary spastic paraplegia.

Adolescent↗
PubMed1991

Mutational analysis of a virulence locus in the E2 glycoprotein gene of Sindbis virus.

The substitution of arginine for serine at position 114 of glycoprotein E2 in several biological and recombinant Sindbis virus mutants was shown previously to attenuate the virus for neonatal mice and also to accelerate virus penetration into BHK cells. To further examine the genetically linked effects on both virus penetration into cultured cells and pathogenesis in vivo, mutants containing each of 16 different amino acid coding changes at this position were generated by site-directed mutagenesis of a full-length cDNA clone of the Sindbis virus genome. Viable virus was recovered following transfection of RNA transcripts from 14 of the clones. Phenotypic analysis of these virus mutants revealed that specific amino acid residues affected either the pathogenesis or penetration phenotype independently or both phenotypes simultaneously. Thus, both the position of a mutation within the E2 sequence and the particular amino acid encoded at that position are important determinants of the mutant phenotypes.

Amino Acid Sequence↗
PubMed2007

Q89R polymorphism in the LDL receptor-related protein 5 gene is associated with spinal osteoarthritis in postmenopausal Japanese women.

STUDY DESIGN: An association study investigating the genetic etiology for spinal osteoarthritis. OBJECTIVE: To determine the association of single-nucleotide polymorphism (SNP) causing an amino-acid change (Q89R) in the low-density lipoprotein receptor-related protein 5 (LRP5) coding region with spinal osteoarthritis. SUMMARY OF BACKGROUND DATA: Wnt/beta-catenin signaling pathway regulates bone density through a Wnt coreceptor LRP5. This pathway is also involved in cartilage development and homeostasis, suggesting that genetic variation in LRP5 gene may affect the pathogenesis of cartilage-related diseases, such as osteoarthritis. METHODS: We evaluated the presence of osteophytes, endplate sclerosis, and narrowing of disc spaces in 357 Japanese postmenopausal women. Missense coding SNP for Q89R of LRP5 gene was determined using TaqMan polymerase chain reaction (PCR) method. RESULTS: We found that subjects without the R allele (QQ; n = 321) had a significantly lower osteophyte formation score than did subjects bearing at least one R allele (QR + RR; n = 36) (7.80 vs. 10.89, P = 0.0019 by analysis of covariance). CONCLUSIONS: We suggest that a genetic variation at the LRP5 gene locus is associated with spinal osteoarthritis, in line with the involvement of the LRP5 gene in the bone and cartilage metabolism.

Aged↗
PubMed1995

The effect of changes in nucleotide sequence coding for the N-terminus on expression levels of ovine growth hormone variants in Escherichia coli.

The expression levels of coding sequences for pituitary growth hormone, introduced into Escherichia coli by genetic manipulation techniques, vary markedly according to the precise sequence introduced. In order to understand the basis of this variation more fully, we have studied the relationship between the level of expression in E. coli of a series of ovine growth hormone variants and the nucleotide sequences coding for their N-terminal regions. Sequence variation resulted from the introduction of deletions, or site-directed mutations, into a plasmid containing the coding sequence for ovine growth hormone preceded by the initiation codon and 25 bases derived from beta-galactosidase or linker regions of plasmid pUC8. The expression levels of the variants varied from less than 0.01% to over 34% of the total cell protein, indicating that changes in the nucleotide sequence close to the initiation codon had a marked effect on expression level. The results of a comparison of closely related sequences in pairs of plasmids giving poor or good expression are consistent with the hypothesis that poor translation of growth hormone mRNAs is caused by the presence of secondary structures close to the initiation codon. Secondary structures are identified that appear to explain the variation in expression levels.

Animals↗
PubMed2005

Genome organization and three kinds of heritable changes: general description and stochastic factors (a review).

Due to the increased knowledge of genome architecture, topology, and the mechanisms of hereditary variability, the list of genetic components has grown. This review outlines the general features and principles of genome organization in diverse organisms. The genome codes, stores, and transfers information in both structurally and dynamically. The genome includes two subsystems of genetic elements: obligatory (genes and gene families) and various types of facultative elements which are predominant the content of the human genome. The features of three kinds of heritable changes: mutations, variations (changes in the number or topography of facultative elements), and epigenetic alterations are described. Facultative elements are the first to react to environmental challenges. Together with epigenetic changes, they implement the operational genomic memory. This review discusses both the role of stochastic factors and the transient features of DNA components.

Animals↗
PubMed2003

The neurobiology of autism: new pieces of the puzzle.

The neurobiologic basis of autism is reviewed, with discussion of evidence from genetic, magnetic resonance imaging, neuropathology, and functional neuroimaging studies. Although autism is a behaviorally valid syndrome, it is remarkably heterogeneous and involves multiple developmental domains as well as a wide range of cognitive, language, and socioemotional functioning. Although multiple etiologies are implicated, recent advances have identified common themes in pathophysiology. Genetic factors play a primary role, based on evidence from family studies, identification of putative genes using genome-wide linkage analyses, and comorbidities with known genetic mutations. The RELN gene, which codes for an extracellular protein guiding neuronal migration, has been implicated in autism. Numerous neuropathologic changes have been described, including macroencephaly, acceleration and then deceleration in brain growth, increased neuronal packing and decreased cell size in the limbic system, and decreased Purkinje cell number in the cerebellum. Abnormalities in organization of the cortical minicolumn, representing the fundamental subunit of vertical cortical organization, may underlie the pathology of autism and result in altered thalamocortical connections, cortical disinhibition, and dysfunction of the arousal-modulating system of the brain. The role of acquired factors is speculative, with insufficient evidence to link the measles-mumps-rubella (MMR) vaccine with autism or to change immunization practices.

Autistic Disorder↗
PubMed1975

An electron microscopic study of the effects of portacaval shunts on the ultrastructure of the rat liver after partial hepatectomy.

The normally quiescent stable adult liver has a generous capacity for reparative hypertrophy and hyperplasia after loss of functional tissue. The large reserve of the liver's functional capacity permits survival of the animal even if over 70 per cent of its liver is removed. It retains an inherent capacity for regenerative growth which subsides once the original organ deficit is restored. This study attempted to resolve the question of whether alteration in hepatic hemodynamics affects the regenerative stimulus of the liver after partial (70 per cent) hepatectomy. It has shown that the liver remnant regenerates after reduction of portal blood flow by construction of a portacaval anastomosis. The diversion of blood from the liver exerts its own histologic and electron microscopic effects on the liver. Reduction of portal blood flow affects the temporal patterns of regeneration after partial hepatectomy but does not prevent completion of the regenerative process. Correlation of this study with the biochemical data available in the literature indicates that the structural changes in the cellular organelles during the process of regeneration reflect dynamic biochemical events that are based on a predetermined genetic code representing the key to life that is uniquely found in the liver.

Animals↗
PubMed1995

Decreased profilaggrin expression in ichthyosis vulgaris is a result of selectively impaired posttranscriptional control.

Ichthyosis vulgaris is an autosomal dominant disorder of keratinization characterized by mild hyperkeratosis and reduced or absent keratohyalin granules in the epidermis. Profilaggrin, a major component of keratohyalin granules, is reduced or absent from the skin of individuals with ichthyosis vulgaris. In this report, we have further characterized the molecular basis of low profilaggrin expression, which occurs in this disease. In situ hybridization revealed little profilaggrin mRNA in ichthyosis vulgaris-affected epidermis. In keratinocytes cultured from the epidermis of affected individuals, the abundance of profilaggrin was reduced to less than 10% of normal controls, while the mRNA level was decreased to 30-60% of controls. Expression of K1 and loricrin, other markers of epidermal differentiation, were not affected. Nuclear run-on assays indicated that the decrease in mRNA levels was not caused by aberrant transcription. Nucleotide sequencing of 5'-upstream, 3'-non-coding, and flanking regions of the profilaggrin gene from ichthyosis vulgaris-affected individuals revealed only minor changes, probably due to genetic polymorphisms. Our results indicate that defective profilaggrin expression in ichthyosis vulgaris is a result of selectively impaired posttranscriptional control.

Adult↗