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PubMed2005

Role of interaction between variants in the PPARG and interleukin-6 genes on obesity related metabolic risk factors.

The combined effect of Peroxisome proliferator-activated receptor gamma (PPARG) Pro/Ala and interleukin-6 G174C gene variants, was evaluated in 429 Caucasian subjects in order to determine whether subjects carrying both variants were at different risk for obesity. In particular, the combined contribution of these two variants (both independent and interaction effects) to the total variation of obesity-related factors was estimated. All subjects were genotyped for codon 12 Pro/Ala locus variability and for the interleukin-6-174 C/G promoter polymorphism. Subjects with the Ala variant had significantly lower BMI, insulin resistance, triglyceride levels than those without. Furthermore, subjects with Ala variant had significantly lower IL-6 levels (0.88 +/- 0.9 vs 1.61 +/- 2.25 pg/ml; p = 0.041). In contrast, the IL6-C variant was significantly associated with lower plasma IL-6 and with lower total cholesterol levels but was not significantly associated with any other obesity risk factors. Indeed, subjects carrying both PPARG and IL-6 gene variants, had a clearly more favourable profile of obesity related risk factors than subjects with one variant, having Ala+/C+ carriers lower BMI (22.8 +/- 2.3 vs 24.14 +/- 1.9; f = 5.31; p < 0.005), insulin resistance (1.49 +/- 0.70 vs 2.13 +/- 0.92; f = 4.342; p = 0.038) and triglyceride levels (79.15 +/- 32.9 vs 98 +/- 6.73 mg/dl; f = 3.120; p < 0.005). These findings suggest that the effect of the two genetic variants on 'obesity related' factors is additive.

Adult↗

PubMed2005

Grey variants of the live vaccine strain of Francisella tularensis lack lipopolysaccharide O-antigen, show reduced ability to survive in macrophages and do not induce protective immunity in mice.

Francisella tularensis live vaccine strain (LVS) produces two colony types when grown on solid media, often referred to as blue variants (BV) and grey variants (GV). Whereas blue variant bacteria possessed a lipopolysaccharide O-side chain, grey variant bacteria lacked O-side chains. Grey variant bacteria appeared in stationary phase bacterial cultures and could be identified using a novel FACS-based assay. Compared to blue variant bacteria, grey variants showed a reduced ability to infect and survive in macrophages. The immunisation of mice with blue variant bacteria, but not grey variant bacteria, induced protective immunity towards fully virulent F. tularensis.

Animals↗

PubMed2004

Many amino acid substitution variants identified in DNA repair genes during human population screenings are predicted to impact protein function.

Over 520 different amino acid substitution variants have been previously identified in the systematic screening of 91 human DNA repair genes for sequence variation. Two algorithms were employed to predict the impact of these amino acid substitutions on protein activity. Sorting Intolerant from Tolerant (SIFT) classified 226 of 508 variants (44%) as "Intolerant." Polymorphism Phenotyping (PolyPhen) classed 165 of 489 amino acid substitutions (34%) as "Probably or possibly damaging." Another 9-15% of the variants were classed as "Potentially intolerant or damaging." The results from the two algorithms are highly associated, with concordance in predicted impact observed for approximately 62% of the variants. Twenty-one to thirty-one percent of the variant proteins are predicted to exhibit reduced activity by both algorithms. These variants occur at slightly lower individual allele frequency than do the variants classified as "Tolerant" or "Benign." Both algorithms correctly predicted the impact of 26 functionally characterized amino acid substitutions in the APE1 protein on biochemical activity, with one exception. It is concluded that a substantial fraction of the missense variants observed in the general human population are functionally relevant. These variants are expected to be the molecular genetic and biochemical basis for the associations of reduced DNA repair capacity phenotypes with elevated cancer risk.

Algorithms↗

PubMed2005

Evaluation of sequence variants in the pre-B cell leukemia transcription factor 1 gene: a positional and functional candidate for type 2 diabetes and impaired insulin secretion.

Pre-B cell leukemia transcription factor 1 (PBX1) encodes a homeodomain containing protein that is essential for pancreatic development and interacts with insulin promoter factor 1 to regulate insulin secretion. PBX1 maps to chromosome 1q22, a region with replicated linkage to type 2 diabetes (T2DM). We screened for sequence variation in nine exons, intronic regions flanking the exons, the 3' untranslated region (3' UTR), as well as 1-kb upstream of exon 1 in 16 Caucasians and 16 African American individuals with T2DM. We evaluated 18 variants including the nonsynonymous substitution G21S in exon 1, one 4 bp insertion/deletion, and one 7 bp insertion/deletion. We typed 10 variants on the basis of frequency and linkage disequilibrium patterns unrelated Caucasian subjects with T2DM and controls, and nine common variants in 129 Caucasian individuals for whom we had detailed assessments of insulin action and insulin secretion. We typed four common variants in African Americans individuals and additional SNPs in pooled DNA samples from both populations. No coding variant was associated with diabetes and no association was found among African American subjects. However, three variants in Caucasians (78287, 91227, and 252050 bp) were associated with T2DM (p<0.05), as were four marker haplotypes that included intron 2 variants. Additionally, three variants including G21S (61 bp) and the diabetes associated SNP at 78287 were significant determinants of insulin sensitivity (S(I)) in interaction with body mass index (p<0.02). Sequence variants in different locations of the PBX1 gene may have modest pleiotropic effects on T2DM susceptibility in Caucasians.

Black People↗

PubMed2002

Alternatively spliced variants of the follicle-stimulating hormone receptor gene in the testis of infertile men.

OBJECTIVE: To investigate whether or not alternatively spliced variants of the FSH receptor gene occur in human testis and whether the presence of the splicing variants is associated with spermatogenic defects and serum FSH concentration in infertile men. DESIGN: A prospective case control study. SETTING: An IVF clinic and infertility laboratory at a university hospital. PATIENT(S): Forty-three infertile patients undergoing testicular biopsy. INTERVENTION(S): Total RNA was extracted from the testicular tissues and used for reverse transcriptase-polymerase chain reaction (RT-PCR). MAIN OUTCOME MEASURE(S): Expression pattern was analyzed by nested RT-PCR using primers designed to amplify a fragment of FSH receptor gene. PCR products of splicing variants were cloned and sequenced. RESULT(S): The PCR products showed three kinds of additional bands corresponding to alternatively spliced isoforms of the FSH receptor gene. Exon 9 deleted variant was detected in all patients and inclusion variant of small extra exon was detected in 64% (9/14) of the patients with normal spermatogenesis and 34% (10/29) of the patients with spermatogenic defects. The presence of inclusion variant was not significantly associated with spermatogenic defects but was associated with a low level of serum FSH. On the other hand, exon 6 deleted variant was detected in only one patient having a high level of FSH concentration (30 IU/L) and Sertoli cell only syndrome. CONCLUSION(S): We identified three different types of alternatively spliced variants of the human FSH receptor. However, it is not clear whether or not there is an association between three variants and spermatogenic defects.

Alternative Splicing↗

PubMed2000

No association between body mass index and beta(3)-adrenergic receptor variant (W64R) in children with premature pubarche and adolescent girls with hyperandrogenism.

OBJECTIVE: To determine if the Trp(64)Arg (W64R) variant of the beta(3)-adrenergic receptor (ADRB3) could be used as a genetic marker to define risk for polycystic ovary syndrom (PCOS) and/or obesity in children and adolescents. DESIGN: Association study. SETTING: Academic research environment. PATIENT(S): Children referred for evaluation of premature pubic hair (n = 63), adolescent girls referred for evaluation of hirsutism and/or oligomenorrhea (n = 33), and healthy adult controls (n = 67). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Relationship of body mass index (BMI) to presence or absence of W64R variant and frequency of W64R variant in our patient population. RESULT(S): Body mass index (kg/m(2)) was determined for 63 children (55 girls and 8 boys) and 33 adolescent girls. Presence or absence of the W64R variant was assayed by polymerase chain reaction (PCR) amplification followed by allele-specific restriction fragment digest. Twelve subjects and 11 healthy controls were found to be heterozygous for the W64R variant. One subject was found to be homozygous for the W64R variant. Allele frequency for the W64R variant was comparable between patients and controls. Among the patients, mean BMI values were not different between carriers and noncarriers. CONCLUSION(S): Although other studies suggest that the W64R variant is associated with the development of obesity and insulin resistance, we cannot demonstrate that it has a major effect on BMI in children with premature pubarche or in adolescent girls with hyperandrogenism. Serial observations are necessary to determine if this variant predicts the development of obesity and/or PCOS in adulthood.

Adolescent↗

PubMed1999

Periodic appearance of a predominant variant antigen type during a chronic Giardia lamblia infection in a mouse model.

Giardia lamblia (syn. Giardia duodenalis, Giardia intestinalis) infections are associated with continuous antigenic variation of the parasite which is mediated by the parasite's major surface antigen, named variant surface protein. Offspring mice and corresponding mothers were infected with G. lamblia clone GS/M-83-H7 (expressing variant surface protein H7) and various parameters of this infection were assessed in a long-term follow-up investigation. Our experimentation revealed that variant surface protein H7-type trophozoites were replaced by new variant-type trophozoites during the early stage of infection (around day 8 p.i.), but the original variant-type re-emerged at at least two time-points during the later stages of infection (at days 22 and 42 p.i.). Such periods of variant surface protein H7-type trophozoite re-expansion were accompanied by transient production of intestinal IgA against variant-specific epitopes on a 314-aa N-terminal region of variant surface protein H7. At late stages of infection (between days 42 and 200 p.i.), most mice produced intestinal IgA against both variant surface protein H7 and other antigens of the parasite. At these stages, infection seemed to be resolved in most mice, but occasional reappearance of relatively high (at day 64 p.i.) or at least detectable (at days 80 and 120 p.i.) amounts of intestinal parasites indicated that G. lamblia GS/M-83-H7 infections in mice may enter into a latent chronic phase which is interrupted by sporadic breakthroughs of parasite growth.

Animals↗

PubMed2002

Comparison of four variants of a major allergen in hazelnut (Corylus avellana) Cor a 1.04 with the major hazel pollen allergen Cor a 1.01.

The aim of this study was to produce the Bet v 1-related major hazelnut allergen Cor a 1.0401 and variants thereof as recombinant allergens, and to compare their immuno-reactivity with the major hazel pollen allergen using sera of patients whose hazelnut allergy recently was confirmed by double-blind placebo-controlled food challenges (DBPCFC) in a multicenter study. Total RNA was isolated from immature hazelnuts and transcribed into cDNA. Full length coding DNA obtained by PCR-strategy was subcloned into pTYB11 vector and expressed in E. coli ER2566 cells. Native non-fusion target proteins were purified by DTT-induced self-cleavage of the intein-tagged N-terminal fusion proteins. IgE reactivity of the recombinant allergens was tested by enzyme allergosorbent test (EAST), EAST-inhibition, immunoblot-inhibition and histamine release assays. Four recombinant allergens were produced showing deduced amino acid sequence identities among each other of 97-99%, and were considered as variants Cor a 1.0401 (GenBank Accession no.: AF136945), Cor a 1.0402 (AF323973), Cor a 1.0403 (AF323974) and Cor a 1.0404 (AF323975). Cor a 1.0402 and 03 only differed in a C4S exchange. Cor a 1.0404 had a unique proline residue in position 99. Surprisingly, only 63% identity was revealed with hazel pollen Cor a 1. EAST with 43 sera of patients with positive DBPCFC to hazelnut indicated IgE reactivity to Cor a 1.0401 in 95% of the sera, to Cor a 1.0402 in 93%, to Cor a 1.0403 in 91%, and in only 74% of the sera to the proline variant Cor a 1.0404. The allergenic activity of the four variants was confirmed by histamine release assays in 15 hazelnut-allergic patients stimulated with the four variants and controls. Eleven sera were positive with extract from native hazelnut, 13 with rCor a 1.0401, 12 with rCor a 1.0402, 11 with rCor a 1.0403, and only two with rCor a 1.0404 containing the proline exchange. The high IgE binding variant Cor a 1.0401 showed only partial IgE cross-reactivity with pollen Cor a 1. IgE-binding and histamine release capacity led to a concordant ranking of the allergenic activity of the recombinant variants: Cor a 1.0401>Cor a 1.0402 and 03>Cor a 1.0404 (the proline variant). Similar results for Cor a 1.0402 and 03 suggest a minor influence in IgE binding of cysteine in position 4, whereas proline in position 99 appears to be responsible for the decrease in IgE reactivity in Cor a 1.0404. It appears that the epitopes of hazelnut Cor a 1.04 are less related to pollen Cor a 1 than to Bet v 1 from birch pollen. Low IgE binding variants or mutants of Cor a 1.04 are candidate compounds for developing a novel and safe approach of specific immunotherapy of hazelnut allergy.

Allergens↗

PubMed1999

TRAF-3 mRNA splice-deletion variants encode isoforms that induce NF-kappaB activation.

Although TRAF-3 gene products are required for signaling in T-B cell collaboration, full-length TRAF-3 appears to lack signaling function in transient transfection assays that measure NF-kappaB activation. However, the TRAF-3 gene also encodes at least three mRNA splice-deletion variants that predict protein isoforms (delta25aa, delta52aa and delta56aa) with altered zinc (Zn) finger domains and unknown functional capacities. To determine whether TRAF-3 splice-deletion variants may transmit activating receptor signals to the nucleus, cDNAs for five additional splice-variant isoforms (delta27aa, delta83aa, delta103aa, delta130aa and delta221aa) were cloned from a TRAF-3+ lymphoma and the expression and function of each of the eight TRAF-3 splice-deletion variants was analyzed. Among the splice-deletion variants, TRAF-3 delta130 mRNA is expressed by tonsillar B cells and by each of a panel of B and T cell lines. TRAF-3 delta221 protein is expressed by tonsillar B cells and by each of the lymphocytic lines. The functional effect of over-expressing each TRAF-3 splice-deletion variant on NF-kappaB activation was studied in 293 T cells. Seven of the TRAF-3 splice-deletion variants, such as TRAF-3 delta130, induce substantial NF-kappaB-driven luciferase activity (80-500 fold). In contrast, TRAF-3 delta221 (in which the complete Zn finger domain is absent) fails to induce NF-kappaB activation. Although full-length TRAF-3 alone is inactive, it augments the functional effects of the seven activating TRAF-3 splice-deletion variants (1.4-5 fold). These data indicate that alterations of the Zn finger domains render the TRAF-3 splice-deletion variants capable of inducing NF-kappaB activation and that full-length TRAF-3 augments their signaling.

Alternative Splicing↗

PubMed2001

Complete nucleotide sequence and cell-line multiplication pattern of the attenuated variant CH2195LA of Japanese encephalitis virus.

Strain-specific determinant of Japanese encephalitis virus (JEV) can be different among each virulence phenotype. We reported previously that the attenuated variant CH2195LA compared with the non-attenuated variant CH2195SA had four amino acid differences in E protein (E-85, E-306, E-331, and E-387) (Wu, S.-C., Lian, W.-C., Hsu, L.-C., Liau, M., 1997. Japanese encephalitis virus antigenic variants with characteristic differences in neutralization resistance and mouse virulence. Virus Res. 51, 173-181). Our present study determined the complete nucleotide sequences of these two variants and found another five amino acid changes in the nonstructural gene regions, including NS2A-215, NS3-350, NS4B-196, NS4B-197, and NS4B-198. The complete nucleotide sequences of the attenuated variant CH2195LA were compared with the non-attenuated variant CH2195SA and other 13 JEV strains. CH2195LA was mostly close to CH2195SA and JaOArS982, and phylogenetically distant to SA14-14-2, SA14-2-8, and RP-2ms of the attenuated JEV strains. The multiplication patterns for CH2195LA compared with CH2195SA in other seven cell lines were different from Vero cells. Relative fitness vector analysis based on a mixture of both variants during cell passage indicated the attenuated variant CH2195LA showed increased viral fitness in Vero cell adaptation. These results revealed that the attenuated variant CH2195LA was unique to culture in Vero cells.

Amino Acid Substitution↗

PubMed2002

Estrogen receptor alpha mRNA variant lacking exon 5 is co-expressed with the wild-type in endometrial adenocarcinoma.

BACKGROUND: Endometrial adenocarcinoma is a typical estrogen-dependent neoplasia. The molecular mechanisms underlying carcinogenesis in the endometrium are still largely unknown. Recently, estrogen receptor (ER) mRNA splicing variants have been investigated in several normal and neoplastic human tissues. It has been suggested that the variant receptors compete with the wild-type receptors and thereby modulate the effects of estrogens and related steroids. OBJECTIVE: To investigate the possible expression of the ER alpha mRNA variant-type lacking exon 5 (ERDelta5) in endometrial adenocarcinoma and peritumoral tissues, non-neoplastic endometrium of healthy women served as control. STUDY DESIGN: The study included 16 patients divided in two groups. The first group (n=6) was submitted to hysteroscopy and endometrial biopsy for metrorrhage, showing normal proliferative (n=2) or secretory (n=4) endometrium, the second group (n=10) included patients submitted to hysterectomy for endometrial adenocarcinoma (stages Ib-IIIb). In this latter group, specimens from peritumoral tissues were also analyzed (n=3). Characterization of the variant and wild-type alpha estrogen receptor transcripts was performed by RT-PCR with primers located in exons 4 and 6, followed by southern hybridization with probes directed to a specific 29 nucleotide sequence of exon 6, internal to the amplified fragments. RESULTS: The ER alpha mRNA variant was co-expressed with the wild-type ER in five or six samples of non-neoplastic endometrium and in 10/10 cases of adenocarcinoma, with a more intense hybridization signal corresponding to the wild-type 439bp band compared to the variant-type 300bp band. Specimens from peritumoral tissue also expressed the variant ERDelta5 along with wild-type ER. CONCLUSION: The presence of alpha mRNA variant lacking exon 5 in both normal and endometrial adenocarcinoma do not support a major role of variant estrogens receptors in the biology of endometrial cancer.

Adenocarcinoma↗

PubMed2000

Human follicle stimulating hormone receptor variants lacking transmembrane domains display altered post-translational conformations.

Variant splicing of gonadotropin receptor mRNA commonly occurs, however expression of receptor protein variants and their trafficking has yet to be studied in detail. To determine receptor variant trafficking and intracellular processing in mammalian cells, the intracellular fate of intentionally truncated variants of human follicle stimulating hormone receptor (hFSH-R) expressed in CHO cells was examined. Monoclonal antibodies (mAbs) were made against the hFSH-R's extracellular domain (ECD) expressed in insect cells. Four mAbs 106.156, 106.290, 106.318, and 106.263 were chosen as probes. Epitope mapping using synthetic peptides, and truncated hFSH-R variants revealed that mAb 106.156 bound to ECD residues 183-220, while mAbs 106.318, 106.290, 106.263 bound ECD residues 300-331. Immunofluorescence microscopy showed that mAbs 106.318 and 106.156 stained the surface of fixed, intact CHO cells expressing wild type hFSH-R. However, following cell permeabilization all four antibodies stained hFSH-R in Golgi and endoplasmic reticulum. Permeabilized cells expressing truncated variants ECD213 and ECD254 showed staining accumulated in the endoplasmic reticulum/nuclear envelope continuum. ECD335/His was found to accumulate in extended endoplasmic reticulum (ER). The ER location of ECD335/His was confirmed by double labeling experiments with concanavalin A and ECD mAb. Glycosidase digestion followed by Western blot analysis show ECD213 and ECD335/His to be glycosylated, but not ECD254. Both glycosylated truncated hFSH-R variants were sensitive to peptide-N-glycanase F and endoglycosidase H but insensitive to neuraminidase indicating that these variants possess high mannose type oligosaccharides. Thus truncated hFSH-R variants do not reach the medial or trans Golgi where high mannose oligosaccharides are trimmed and sialic acid is added. These data suggest that the conformation the ECD of the wild type receptor is different from the ECD alone expressed in the endoplasmic reticulum. This information suggests that the ECD serves two distinct roles; the first is to bind FSH and the other is likely to contact the endodomain of the receptor, which presumably leads to activation of the endodomain for signal transduction.

Amino Acid Sequence↗

PubMed2002

A splice variant of glutamate transporter GLT1/EAAT2 expressed in neurons: cloning and localization in rat nervous system.

Rapid uptake of synaptically released glutamate via the high affinity glutamate transporter 1 (GLT1; EAAT2) is important for limiting transmitter signalling and prevents a harmful receptor overstimulation. So far, in the adult brain GLT1 protein has only been detected in astrocytes. Here, we describe the cDNA cloning of a variant of GLT1 from rat brain which is generated by alternative splicing at the 3'-end of the GLT1 cDNA. Reverse transcription-polymerase chain reaction revealed that the GLT1 variant message was present not only in brain, but also in peripheral organs. Northern blot analysis showed that in brain the mRNA of GLT1 (approximately 11 kb) is predominant while in the retina the mRNA of GLT1 variant (approximately 12.5 kb) prevails. In situ hybridization using cRNA and oligonucleotide probes, and immunocytochemistry using an antibody against a synthetic GLT1v peptide were applied in order to identify the cell types expressing GLT1 variant in the adult rat nervous system. GLT1 variant is preferentially expressed in neurons of the CNS and PNS, but is also detected in glial cells (oligodendrocytes, ependymal cells, epithelial cells of the plexus choroideus, satellite cells, and Schwann cells). In contrast to GLT1, GLT1 variant was only occasionally detected in astrocytes. Immunolabelling revealed a preferentially cytoplasmic (frequently granular) staining of neurons and glial cells, suggesting a localization of GLT1 variant protein in vesicle membranes. The studies provide evidence that the cellular expression of the GLT1 variant in the CNS is almost complementary to that of GLT1 and that the GLT1 variant does not seem to be restricted to the CNS.

Alternative Splicing↗

PubMed1982

Human albumin variants. Nomenclature of allotypes observed in Europe and quantitative estimation of their relative mobilities.

In order to clarify the actual nomenclature of the albumin allotypes in French and Italian populations we compared the samples collected in our laboratory to those kindly supplied by Dr. Porta (Italy) with reference to albumin variants classified in starch gel electrophoresis using three buffer systems by Weitkamp. The inherited human albumin variants can be classified on the basis of their relative mobilities on cellulose acetate electrophoresis compatively to human transferrin mobility. The relative mobility of each variant can be expressed by the following ratio: migration distance of the variant versus migration distance of the normal albumin where zero represents the transferrin mobility. Using three buffers system at pH 8.6, 5.0 and 6.9, it is possible to distinguish some albumin variants having a same mobility at alkaline pH and different mobilities at acidic pH. In the european area, eleven albumin variants are distinguishable on the basis of their relative mobilities at different pH: four Fast moving variants: Gent, Vanves (a new variant described here), Reading and CN/BL, and seven Slow moving variants: MI/MI Slow, GE/CT, SO/BS (or D type), Pollibauer, Gainesville, Roma and B type. Thirty-six sera from unrelated subjects with genetic bisalbuminemia were analyzed in our laboratory. Their distribution was as follows: B type (22), Pollibauer (9), SO/BS (2), Gainesville (1), Gent (1) and Vanves type (1). The frequency of bisalbuminemia was 0.35 per 1,000 in a population of 19,949 blood donors.

Blood Protein Electrophoresis↗

PubMed2001

Variants of the 5'-untranslated region of the bovine growth hormone receptor mRNA: isolation, expression and effects on translational efficiency.

The growth hormone receptor (GHR) gene in cattle is expressed as multiple GHR mRNA variants that differ in the 5'-untranslated region (5'-UTR). Three GHR mRNA 5'-UTR variants (named 1A, 1B, and 1C) were isolated in previous studies. Six additional GHR mRNA 5'-UTR variants (named 1D, 1E, 1F, 1G, 1H, and 1I) were discovered in the present study by using rapid amplification of cDNA ends (RACE). Ribonuclease protection assays (RPA) indicated that variant 1A was exclusively expressed in liver, variant 1F was expressed in liver and muscle, and most of the remaining GHR 5'-UTR variants were expressed in a variety of tissues including liver and muscle. The RPA also indicated that in liver and skeletal muscle, two important GH target tissues, the most abundant GHR mRNA 5'-UTR variants were 1A and 1B (liver) and 1B and 1C (muscle), respectively. In vitro translation assays indicated that the GHR 5'-UTR variants also differed in their effects on the translation of a luciferase reporter mRNA. Notably, the GHR 5'-UTR 1B, which is a highly expressed GHR 5'-UTR variant in vivo, strongly inhibited translation of the luciferase reporter mRNA. The observations in the present study suggest that GHR expression in the bovine may be controlled by translational mechanisms in addition to complex transcriptional mechanisms.

5' Untranslated Regions↗

PubMed2003

T594M variant of the epithelial sodium channel beta-subunit gene and hypertension in individuals of African ancestry in South Africa.

BACKGROUND: The T594M variant of the beta-subunit of the sodium epithelial channel (ENaC) gene may contribute to hypertension in individuals of African origin. METHODS: A case-control study was performed to assess the role of the ENaC gene variant as an independent risk factor for hypertension in subjects of African ancestry. The effects of the ENaC gene variant on ambulatory blood pressure (BP) in hypertensive individuals and on office BP in hypertensive individuals and control subjects were also assessed. A total of 519 hypertensive patients with 24-h ambulatory BP (ABP) values determined while off medication, and 514 normotensive South African individuals of African ancestry were genotyped for the T594M polymorphism of the ENaC gene. RESULTS: A total of 22 (4.2%) hypertensive participants compared with 23 (4.5%) normotensive participants possessed the T594M variant (odds ratio = 1.06, confidence interval = 0.58 to 1.92, not significant). A similar genotype frequency distribution was noted in subjects representing the two predominant chiefdoms (Nguni and Sotho) in both case and control groups. No differences in frequency distribution of the T594M variant were noted with respect to either body mass index or gender. There were no differences in clinic or ambulatory mean, day, or night BP between hypertensive patients with or without the variant. Similarly, no differences were noted in clinic BP between control subjects with or without the variant. Other phenotypic parameters (including age and hypertension duration and severity) were also similar among hypertensive patients with or without the variant. CONCLUSION: These results do not support an important role for the T594M variant of the ENaC gene contributing to either the development or severity of hypertension in subjects of African ancestry.

Black People↗

PubMed2003

A mitochondrial DNA sequence variant associated with schizophrenia and oxidative stress.

We have previously reported a changed mitochondrial (mt) gene expression in brain from patients with schizophrenia [Schizophr. Res. 14 (1995) 203]; now, we describe the distribution in the mtDNA from lymphocytes of a heteroplasmic sequence variation that was originally found in the mtDNA from the postmortem brain of a patient with schizophrenia. The variant is m.12027T>C and results in the change from isoleucine to threonine at position 423 of the ND4 subunit of NADH-ubiquinone reductase. Using a PCR-RFLP method, we have determined the heteroplasmy as the ratio of variant to total (variant ratio) at m.12027 in 184 controls and 181 patients with schizophrenia as well as 24 postmortem brain samples. The distribution of variants is bimodal having peaks at variant ratios of 0.262 and 0.732. The variant-rich fraction is very significantly associated with schizophrenia in males (47%), while there is only 18% in control males. There are significantly more variant-rich control females (36%) than control males (18%), suggesting that the female population is less sensitive to the presence of a variant in terms of liability to schizophrenia. In variant-rich samples from postmortem brain originating from both sexes, there is an increased superoxide production, suggesting that the variation contributes to oxidative stress. Antioxidant glycosides, such as quercetin rutoside, quench the superoxide production without (in contrast to neuroleptic drugs) interfering with the electron transfer activity of the reductase.

Adult↗

PubMed1997

Co-expression of MDR-associated markers, including P-170, MRP and LRP and cytoskeletal proteins, in three resistant variants of the human ovarian carcinoma cell line, OAW42.

Variants of the human ovarian carcinoma cell line, OAW42, exhibiting low-level intrinsic resistance (OAW42-SR) and drug-induced higher-level resistance (OAW42-A1 & OAW42-A), were studied along with a sensitive clonal population (OAW42-S) which was isolated from OAW42-SR. Expression of the MDR-associated protein P-170, the more recently discovered LRP (lung resistance-related protein) and MRP (multidrug resistance-associated protein), topoisomerase II alpha and beta, GST pi and the cytoskeletal proteins, cytokeratin 8 and vimentin, were studied (using immunocytochemistry and Western blotting techniques) in conjunction with drug (doxorubicin) accumulation and subcellular distribution. Expression of mRNA for P-170, MRP, topoisomerase 11 alpha and beta and GST pi was studied using RT-PCR (reverse transcriptase polymerase chain reaction). Results indicate differential co-expression of four MDR-associated parameters (P-170, MRP, LRP and reduced topoisomerase II alpha and beta) in the OAW42-SR and OAW42-A1 variants, whereas resistance in the OAW42-A variant appeared to be mainly P-170 mediated. Comparable amounts of MRP and greater amounts of LRP were detected in the OAW42-S cells compared to the OAW42-SR variant (which showed increased resistance compared to the OAW42-S cells), but all cell lines expressed similar low-level amounts of MRP mRNA (by RT-PCR). GST pi levels did not differ markedly between variants. Increased levels of the cytoskeletal proteins were observed with increasing levels of resistance. The relative resistance of the variants, OAW42-SR and OAW42-A1, compared with OAW42-S was seen to change during increased serial passaging of the cells. There was greater drug accumulation by the sensitive OAW42-S cell line compared with that of the resistant variants, particularly the most highly resistant OAW42-A cells. Both verapamil and cyclosporin A effectively restored the accumulation defects seen in the resistant variants, cyclosporin A being the more effective of the two. Sub-cellular location of drug was predominantly in the nucleus with maximum levels seen in the sensitive OAW42-S variant and minimum levels in the most resistant OAW42-A clone.

ATP Binding Cassette Transporter, Subfamily B, Mem↗