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PubMed2026

Loss of interruption in the HTT CAG repeat is associated with somatic expansion and loss of medium spiny neurons in Huntington's disease.

Synonymous loss-of-interruption variants in the expanded CAG repeat sequence of Huntingtin (HTT) accelerate the clinical onset and progression of Huntington's disease (HD). Medium spiny neurons (MSNs) are gradually lost in HD and undergo selective somatic CAG expansion, but it is unclear how somatic expansion relates to MSN pathology. Here, we show that MSNs with large (111-150 CAG) and very large (>150 CAG) somatic expansions are rare in early manifest HD but accumulate in proportion with duration of disease. In patients with the deleterious CAG-CCG loss-of-interruption (CAG-CCG LOI) modifier, the proportion of MSNs with large and very large expansions is increased ∼5-fold despite reduced small somatic expansions in blood, and caudate MSN counts are reduced. Our findings suggest that increased somatic CAG expansion contributes to accelerated striatal MSN pathology and onset of HD but that MSNs with very large genomic CAG expansions can persist among surviving neurons of the HD brain.

Huntington’s disease↗
PubMed1998

Analysis of the insulin receptor gene tyrosine kinase domain in obese patients with hyperandrogenism, insulin resistance and acanthosis nigricans (type C insulin resistance).

OBJECTIVE: To test the hypothesis that the triad of hyperandrogenism, insulin resistance and acanthosis nigricans (HAIR-AN syndrome) in the presence of obesity, also known as type C insulin resistance (type C), is caused by mutations at the tyrosine kinase domain of the insulin receptor gene. DESIGN: A candidate gene approach to study the molecular basis for a syndrome of obesity. SUBJECTS: 15 patients with type C insulin resistance and 25 control individuals. MEASUREMENTS: Analysis of polymerase chain reaction (PCR) products of exons 17 to 21 of the insulin receptor gene, comprising the tyrosine kinase domain, for single strand conformational polymorphisms (SSCP) and sequence analysis of exons with variant SSCP patterns. RESULTS: A synonymous C to T substitution in position 3 of codon 984, which does not alter the amino acid predicted, was found in one patient and in four of 25 control individuals. CONCLUSION: Type C insulin resistance is not commonly caused by mutations in the tyrosine kinase domain of the insulin receptor gene.

Acanthosis Nigricans↗
PubMed2002

Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate receptor.

The glutamatergic system is the major excitatory neurotransmitter system in the CNS. Glutamate receptors, and in particular N-methyl-D-aspartate (NMDA) receptors, have been proposed as mediators of many common neuropsychiatric phenotypes including cognition, psychosis, and degeneration. We have reconstructed the genomic structure of all five genes encoding NMDA receptors in silico. We screened each for sequence variation and estimated the allele frequencies of all detected SNPs in pooled samples of 184 UK Caucasian schizophrenics and 184 UK Caucasian blood donor controls. Only a single non-synonymous polymorphism was found indicating extreme selection pressure. The rarity of non-synonymous changes suggests that such variants are unlikely to make a common contribution to common phenotypes. We found a further 26 polymorphisms within exonic or adjacent intronic sequences. The minor alleles of most of these have a relatively high frequency (63% above 0.2). These SNPs will therefore be suitable for studying neuropsychiatric phenotypes that are putatively related to NMDA dysfunction. Pooled analysis provided no support for association between any of the GRIN genes and schizophrenia.

Base Sequence↗
PubMed2001

Single nucleotide polymorphisms in exons of the apo(a) kringles IV types 6 to 10 domain affect Lp(a) plasma concentrations and have different patterns in Africans and Caucasians.

Lipoprotein(a) [Lp(a)] is a complex of apolipoprotein(a) [apo(a)] and low-density lipoprotein which is associated with atherothrombotic disease. Lp(a) plasma levels are controlled to a large extent by the apo(a) gene locus. Known polymorphisms in the apo(a) gene, including the kringle (K) IV-2 variable number of tandem repeats, explain only part of the large interindividual variability and do not explain the differences in Lp(a) concentrations between major human ethnic groups. Here we performed screening for single nucleotide polymorphisms (SNPs) in exons and flanking intron sequences of the apo(a) K IV types 6, 8, 9 and 10 which represent 1.3 kb of coding sequence in two African (Khoi San, Black South Africans) and one Caucasian (Tyroleans) populations and investigated whether they affect Lp(a) levels. Together, 768 alleles were analyzed. We identified 14 SNPs, including 11 non-synonymous SNPs (eight of which involved conserved residues), one splice site and two synonymous base changes. No sequence variants common to Africans and Caucasians were found. Several of the newly identified SNPs showed significant effects on Lp(a) plasma concentrations. The substitutions S37F in K IV-6 and G17R in K IV-8 were associated with Lp(a) levels significantly below average in Africans. In contrast, the R18W substitution in K IV-9, which occurred with a frequency of 8% in Khoi San, resulted in a significantly increased Lp(a) concentration. Together, our data suggest that several SNPs in the coding sequence of apo(a) affect Lp(a) levels. This indicates that many SNPs may have subtle effects on the gene product.

Alleles↗
PubMed2004

Low prevalence of nonconservative mutations of serum and glucocorticoid-regulated kinase (SGK1) gene in hypertensive and renal patients.

BACKGROUND: The serum- and glucocorticoid-regulated kinase (SGK1) gene is an important mediator of aldosterone action, regulating the expression of the renal epithelial Na(+) channel. In renal failure, blood pressure (BP) is markedly salt-dependent and increases with decreasing renal function. Mutations of the SGK1 gene affecting phosphorylation could be responsible for salt-mediated increases in BP and hypertension-related progression to end-stage renal disease (ESRD). METHODS: The SGK1 gene was analysed for mutations in the exons 4, 5, 8 and 10-12, because of potential phosphorylation sites, in 591 subjects, including 311 ESRD patients (either dialysis or transplanted). In addition, an intron 6 single-nucleotide polymorphism (SNP) described previously was also investigated in this study. Genotyping was performed either by using a strategy based on single strand conformation polymorphism analysis of polymerase chain reaction (PCR) products and subsequent direct sequencing of identified gel shift variants or by using high throughput 5' nuclease allelic discrimination assay. RESULTS: Two SNPs in coding regions of SGK1 potentially influencing the phosphorylation of Sgk1 were identified. Both SNPs were synonymous. The prevalence of the first variant, a previously reported SNP at codon 240 in exon 8, did not differ between ESRD patients (16.3%) and controls (15.7%). There was no association between the SNP in exon 8 and either BP within the control population or progression of renal disease in the ESRD population. The second SNP at codon 398 in exon 12 was identified in one patient only. Intron 6 and exon 8 SNPs were in strong linkage disequilibrium, but did not show any association with either BP or renal diseases. CONCLUSIONS: Based on statistical analysis homozygosity for nonconservative mutations in the coding region of the SGK1 gene is estimated at < 1/300 000 when a white Caucasian population is considered, arguing against an important role of mutations of this coding region in hypertension and hypertension-associated progression of renal disease.

Blood Pressure↗
PubMed2005

Genetic variation in the sand fly salivary protein, SP-15, a potential vaccine candidate against Leishmania major.

SP-15 is a sandfly salivary protein that provides strong protection against cutaneous leishmaniasis, caused by Leishmania major, and has been proposed as a potential vaccine against this disease. To investigate possible antigenic variation in this protein, we examined genetic polymorphism of SP-15 in 100 Phlebotomus papatasi sandflies, from a natural population from Sudan and four laboratory colonies from Egypt, Jordan, Israel and Saudi Arabia. We found that although many variants of SP-15 may be found in nature, differences among them are minimal (mean+/-SD pairwise differences=1.69+/-0.83% for forty nucleotide sequences and 3.06+/-1.13% for thirty amino acid sequence variants). Analysis of proportions of synonymous and non-synonymous substitutions indicated that SP-15 is not under diversifying selection. Our results suggest that a vaccine based on SP-15 protein should result in a uniform immune response.

Amino Acid Sequence↗
PubMed2001

Identification of SNPs in human gamma aminobutyric acid A receptor gamma2 gene.

Gamma aminobutyric acid (GABA) is a major inhibitory neurotransmitter. Because of its importance and diverse functions, studies of single nucleotide polymorphisms in the GABA receptor genes are of great significance, which may produce useful molecular markers for genetic analysis of neurological disease, and possibly lead to the discovery of pathogenic mutations. We identified eleven SNPs in the entire exon regions, immediate intron regions and promoter region of human GABA receptor gamma2 gene by direct sequencing. In this discovery, 2 non-synonymous cSNPs and 1 splicing variant are found.

Evolution, Molecular↗
PubMed2004

Soft tissue giant cell tumor of low malignant potential.

Giant cell tumor of soft tissue (GCT-ST) is a rare tumor first described in 1972 by Salm and Sissons, followed shortly by Guccion and Enzinger. This tumor has been considered to be synonymous with the giant cell variant of malignant sarcoma with frequent local recurrence and metastasis. Recently GCT-ST has been described as a distinct entity of relatively benign prognosis, yet lacking marked atypia and pleomorphism, even in the presence of mitotic activity and vascular invasion. Now some authors think that GCT-ST represents the soft tissue analog of giant cell tumor of bone because of their histological and immunohistochemical similarity. Some reports documented these pathological new findings, but clinical case reports with description of imagings and surgery on the basis of these knowledge are very few. The authors describe the clinical, radiological, morphologic and histopathologial features of a case of GCT-ST occurring primarily in the subcutaneous tissue of the thigh with a review of the literature.

Antigens, Differentiation↗
PubMed2004

Association analysis of two candidate phospholipase genes that map to the chromosome 15q15.1-15.3 region associated with reading disability.

Molecular genetic studies have suggested a reading disability (RD, dyslexia) susceptibility locus on chromosome 15q. We have previously mapped this locus by association to the region surrounding D15S994. Very little is known about the neurobiological processes involved in RD, and therefore selecting positional candidate genes for analysis based upon function is difficult. Nevertheless we were able to identify two functional candidates based upon existing hypotheses. Both were phospholipase genes, phospholipase C beta 2 (PLCB2) and phospholipase A2, group IVB (cytosolic; PLA2G4B). D15S944 is located within PLCB2 and is 1.6 Mb from PLA2G4B. We examined each gene for association using a mixed direct and indirect association approach, a case (n = 164)/control (n = 174) sample, and a partially overlapping sample of 178 RD parent-proband trios from South Wales and England. Mutation analysis revealed 14 sequence variants in PLCB2 and 33 variants in PLA2G4B. All non-synonymous SNPs were genotyped as were SNPs across each gene with maximum distance between SNPs of 6 kb. Case-control analyses revealed modest evidence (0.01 < P < 0.05) for association between a single variant in PLCB2 and two variants in PLA2G4B. However, association was not confirmed in the family based sample. As the latter sample has previously generated replicated significant evidence for association between RD and markers/haplotypes surrounding D15S944, it should have sufficient power to detect association to variants in susceptibility gene itself. We conclude that neither gene accounts for the association signal we previously observed. As these are the only clear cut functional candidate genes in the region, identification of the putative susceptibility locus for RD on 15q will require more methodical non-hypothesis driven positional cloning approaches.

Alleles↗
PubMed2006

Role of common human TRIM5alpha variants in HIV-1 disease progression.

BACKGROUND: The retroviral restriction factor tripartite motif protein (TRIM)5alpha, is characterized by marked amino acid diversity among primates, including specific clusters of residues under positive selection. The identification of multiple non-synonymous changes in humans suggests that TRIM5alpha variants might be relevant to retroviral pathogenesis. Previous studies have shown that such variants are unlikely to modify susceptibility to HIV-1 infection, or the course of early infection. However, the longterm effect of carrying Trim5alpha variants on disease progression in individuals infected with HIV-1 has not previously been investigated. METHODS: In a cohort of 979 untreated individuals infected with HIV-1 with median follow up 3.2 years and 9,828 CD4 T cell measurements, we analysed common amino acid variations: H43Y, V112F, R136Q, G249D, and H419Y. The rate of CD4 T cell decline before treatment was used as the phenotype. In addition, we extended previous work on the in vitro susceptibility of purified donor CD4 T cells (n = 125) to HIV-1 infection, and on the susceptibility of HeLa cells that were stably transduced with the different TRIM5 variants. Haplotypes were analysed according to the most parsimonious evolutionary structure, where two main human TRIM5alpha groups can be defined according to the residue at amino acid 136. Humans present both Q136 and R136 at similar frequency, and additional TRIM5alpha amino acid variants are almost exclusively derived from R136-carrying haplotypes. RESULTS: We observed modest differences in disease progression for evolutionary branches carrying R136-derived haplotypes, and with the non-synonymous polymorphisms G249D and H419Y. In vitro analysis of susceptibility of donor CD4 T cells, and of the various transduced HeLa cell lines supported the absence of significant differential restriction of HIV-1 infection by the various huTRIM5alpha alleles. CONCLUSION: Common human variants of TRIM5alpha have no effect or modest effect on HIV-1 disease progression. These variants occur at sites conserved throughout evolution, and are remote from clusters of positive selection in the primate lineage. The evolutionary value of the substitutions remains unclear.

Adult↗
PubMed2004

A survey of the Th2R and Th3R allelic variants in the circumsporozoite protein gene of P. falciparum parasites from western Thailand.

Allelic variation in the Plasmodium falciparum circumsporozoite protein (CS) gene has been determined by sequencing the immunodominant T-cell epitopes, Th2R and Th3R, from 95 isolates from two malaria-endemic areas in the west of Thailand. Comparison with a reference sequence revealed only non-synonymous point mutations in the two epitope regions. Point mutations were found outside these epitopes in a minority of samples, and all but four were also non-synonymous. A relatively high number of variants, 11 Th2R and 9 Th3R, were detected and comprised some that had not been previously observed. However, the Th2R*05 and the Th3R*01 allelic variants predominated, as they were found in more than 70% of the 101 sequences obtained.

Alleles↗
PubMed1998

[Comparison of the synonymous and non-synonymous substitution rates in various regions of the neuraminidase and hemagglutinin genes of the influenza A virus].

A new, statistically justified approach was used to estimate the synonymous and non-synonymous substitution rates in several antigenic variants of influenza-virus surface proteins. The rates were compared for antigenic and nonantigenic regions of neuraminidase and hemagglutinin, as well as for neuraminidase surface and internal amino acids identified by X-ray analysis. For neuraminidase, the estimation was performed for the first time. The non-synonymous substitution rate was shown to be significantly higher in antigenic than in nonantigenic sites. However, neither subsample of antigenic sites displayed a fixation rate of non-synonymous substitutions higher than that of synonymous substitutions, which would confirm the effect of positive selection on these sites and argue against a neutral evolution character. Specific features of methods used to estimate the substitution fixation rates and problems in their interpretation are discussed.

Amino Acid Substitution↗
PubMed2005

Identification and functional characterization of variants in human concentrative nucleoside transporter 3, hCNT3 (SLC28A3), arising from single nucleotide polymorphisms in coding regions of the hCNT3 gene.

INTRODUCTION: Human concentrative nucleoside transporter 3, hCNT3 (SLC28A3), which mediates transport of purine and pyrimidine nucleosides and a variety of antiviral and anticancer nucleoside drugs, was investigated to determine if there are single nucleotide polymorphisms in the coding regions of the hCNT3 gene. METHODS AND RESULTS: Ninety-six DNA samples from Caucasians (Coriell Panel) were sequenced and sixteen variants in exons and flanking intronic regions were identified, of which five were coding variants; three of these were non-synonymous (S5N, L131F, Y513F) and were further investigated for functional alterations of the resulting recombinant proteins in Saccharomyces cerevisiae and Xenopus laevis oocytes. In yeast, immunostaining and fluorescence quantitation of the reference (wild-type) and variant CNT3 proteins showed similar levels of expression. Kinetic studies were undertaken in yeast with a high through-put semi-automated assay process; reference hCNT3 exhibited Km values of 1.7+/-0.3, 3.6+/-1.3, 2.2+/-0.7, and 2.1+/-0.6 muM and Vmax values of 1402+/-286, 1310+/-113, 1020+/-44, and 1740+/-114 pmol/mg/min, respectively, for uridine, cytidine, adenosine and inosine. Similar Km and Vmax values were obtained for the three variant proteins assayed in yeast under identical conditions. All of the characterized hCNT3 variants produced in oocytes retained sodium and proton dependence of uridine transport based on measurements of radioisotope flux and two-electrode voltage-clamp studies. CONCLUSION: These results suggested a high degree of conservation of function for hCNT3 in the Caucasian population.

Adenosine↗
PubMedDate not supplied

Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies.

The 5-HT(2A)-serotonin receptor is a major molecular target for most atypical antipsychotic drugs as well as most hallucinogens, which can exacerbate psychotic symptoms. In this study, we examined whether random sequence variations in the gene (single nucleotide polymorphisms, SNPs) encoding the 5-HT(2A)-serotonin receptor could explain inter-individual variability in atypical antipsychotic and agonist drug response. We examined the in vitro pharmacology of four non-synonymous SNPs, which give rise to T25N, I197V, A447V, and H452Y variant 5-HT(2A)-serotonin receptors. Our data indicate that these non-synonymous SNPs exert statistically significant, although modest, effects on the affinity and functional effects of several currently approved atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone). Also, the 5-HT(2A) receptor SNPs slightly altered the potency and relative efficacy of a small number of selected agonists (2,5-dimethoxy-4-iodoamphetamine, tryptamine, 5-hydroxytryptamine, m-chlorophenylpiperazine, and 5-methoxy-N, N-dimethyltryptamine). In all, our results show that the in vitro pharmacological effects of the SNPs are drug specific.

Antipsychotic Agents↗
PubMed2002

Influence of interleukin-12 receptor beta1 polymorphisms on tuberculosis.

Host genetic factors may be important determinants of susceptibility to tuberculosis, and several candidate gene polymorphisms have been shown to date. A series of recent reports concerning rare human deficiencies in the type-1 cytokine pathway suggest that more subtle variants of relevant genes may also contribute to susceptibility to tuberculosis at the general population level. To investigate whether polymorphisms in the interleukin-12 receptor (IL-12R) gene predispose individuals to tuberculosis, we studied these genes by single-strand conformational polymorphism analysis and direct sequencing. Although no common polymorphisms could be identified in the IL-12R beta 2 gene ( IL-12RB2), we confirmed four single nucleotide polymorphisms (SNPs; 641A-->G, 684C-->T, 1094T-->C, and 1132G-->C) causing three missense variants (Q214R, M365T, G378R) and one synonymous substitution in the extracellular domain of the IL-12R beta 1 gene ( IL12RB1). All SNPs were in almost perfect linkage disequilibrium (D'=0.98), and two common haplotypes of IL12RB1(allele 1: Q214-M365-G378; allele 2: R214-T365-R378) were revealed. Polymerase chain reaction/restriction fragment length polymorphism and sequence analyses were used to type IL12RB1polymorphisms in 98 patients with tuberculosis and 197 healthy controls in Japanese populations. In our case-control association study of tuberculosis, the R214-T365-R378 allele (allele 2) was over-represented in patients with tuberculosis, and homozygosity for R214-T365-R378 (the 2/2 genotype) was significantly associated with tuberculosis (odds ratio: 2.45; 95% CI: 1.20-4.99; P=0.013). In healthy subjects, homozygotes for R214-T365-R378 had lower levels of IL-12-induced signaling, according to differences in cellular responses to IL-12 between two haplotypes. These data suggest that the R214-T365-R378 allele, i.e., variation in IL12RB1, contribute to tuberculosis susceptibility in the Japanese population. This genetic variation may predispose individuals to tuberculosis infection by diminishing receptor responsiveness to IL-12 and to IL-23, leading to partial dysfunction of interferon-gamma-mediated immunity.

Adult↗
PubMed2006

Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs.

Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.

Adult↗
PubMed1993

Distinction between diffuse cutaneous malignant follicular center cell lymphoma and lymphoid hyperplasia by computerized nuclear image analysis.

The difficult differential diagnosis between the diffuse variants of cutaneous lymphoid hyperplasia (CLH; synonym; pseudolymphoma) and malignant follicular center cell lymphomas (FCCL) often requires a multidisciplinary approach. Eighteen CLH and 11 FCCL, diagnosed by conventional histology and immunophenotyping and subsequently examined with a polymerase chain reaction to show clonal immunoglobulin heavy-chain gene rearrangements, were subjected to a novel type of automated nuclear image analysis. Of all nuclear parameters tested in azure A-stained semithin sections, the mean nuclear profile area (TN) of lymphoid cells was the best criterion to distinguish between CLH and FCCL (p = 9 x 10(-6)). Additional distinctive features, in the order of decreasing significance, were the SD of TN; all chromatin textural parameters combined; and the light and the dark fractions of the central nuclear profile areas. Parameters related to the chromatin pattern were independent of nuclear profile size in FCCL, but not in CLH. Two lesions registered as CLH displayed the nuclear characteristics favoring this diagnosis, but showed B-cell monoclonality at the DNA level. In conclusion, computerized nuclear image analysis is a helpful additional diagnostic tool in the evaluation of diffuse CLH and cutaneous FCCL.

Adolescent↗
PubMed2001

Mutation screening of the metabotropic glutamate receptor mGluR4 (GRM4) gene in patients with schizophrenia.

Disturbances in glutamate function have been implicated in the pathophysiology of schizophrenia. We searched for mutations in the exons of the metabotropic glutamate receptor mGluR4 (GRM4) gene on human chromosome 6p21.3 and evaluated associations between these polymorphisms with schizophrenia in Japanese patients. Nine nuclear variants of 450G > T, 1455T > C, 2202A > G, 2389G > A (Val797 > Ile797), 2890A > G, 3601C > T, 3639C > T, IVS4-36G > A, and IVS5 + 29(CCGGG)1-2, were found. The Val797Ile variant, although found in both the patient and control groups, was rare and the only variant that causes a non-synonymous amino acid change. There was no statistically significant association between any mGluR4 gene polymorphism and schizophrenia. Thus, this study did not provide evidence for the contribution of the mGluR4 gene to schizophrenia in the Japanese.

Adult↗