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PubMed2003

Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B.

YMDD variants of hepatitis B virus (HBV) emerge in some patients with chronic hepatitis B who receive lamivudine. YMDD variants were examined in 794 patients in 4 controlled studies of 1 year's duration. The long-term effects of YMDD variants were examined in a subset of patients treated up to 4 years. YMDD variants were detected by polymerase chain reaction (PCR) and restriction fragment-length polymorphism assays. After 1 year, YMDD variants were detected in 81 (24%) of 335 patients. In these patients, the median serum HBV DNA concentration at 1 year was <20% of the baseline level, and serum alanine transaminase (ALT) levels and liver histologic findings had significantly improved. In patients with YMDD variants who were treated for up to 4 years, median HBV DNA and ALT levels showed improvements. Sex, baseline body mass index, and HBV DNA level were associated with emergence of YMDD variants. Patients with YMDD variants losing clinical response with a significant increase in the HBV DNA and ALT levels may require additional therapy.

Alanine Transaminase↗

PubMed2004

Widespread dissemination in England of a stable and persistent hepatitis B virus variant.

BACKGROUND: Outbreaks of acute hepatitis B among inmates of 6 prisons in 3 regions of northern England occurring from 1992 through 1994 were found to be associated with a single hepatitis B virus (HBV) variant, which was carried by 20 of the 24 case patients. We instigated a study of cases of acute hepatitis B to trace the spread and prevalence of this variant. METHODS: A denaturing gradient gel electrophoresis assay was optimized to detect the HBV variant, and cases of acute HBV infection in 3 regions in England occurring from 1990 through 1996 were screened for its presence. Samples from HBV-transmission incidents that were received for molecular investigation were also tested. RESULTS: The variant was identified in 117 (41%) of the 266 cases of acute hepatitis examined in representative regions in England. In North Humberside, but not in southeast England or the West Midlands, a trend toward an increase in the prevalence of the variant was observed. Furthermore, the same variant was identified in the case patients or the individuals implicated in transmission in 11 (22%) of 51 transmission incidents occurring in England from 1997 through 2002. The spread of the variant was primarily associated with injection drug use. CONCLUSIONS: The finding of a single, genetically identical variant (over the 600 bp sequenced) occupying a large niche among the circulating viruses was unexpected. This finding has major implications for the use of DNA sequencing analysis in the investigation of chains of transmission. The study also highlights the need for better protection of at-risk groups through vaccination against HBV, a strategy that currently achieves poor coverage.

Disease Outbreaks↗

PubMed1998

Evolution of U24 and U36 snoRNAs encoded within introns of vertebrate rpL7a gene homologs: unique features of mammalian U36 variants.

U24 and U36 are members of the box C/D-containing group of antisense snoRNAs which possess long (9-21 nucleotide) conserved stretches of sequence complementarity to 18S and 28S rRNA and act as guides for the site-specific ribose methylation of rRNA. Both U24 and two variants of U36 are encoded within introns of the human and chicken rpL7a genes. We now report that an additional U36 variant is encoded within intron 4 of the human rpL7a gene and that murine homologs of the three human U36 variants are encoded within the same adjacent introns (4, 5, and 6) of the mouse rpL7a gene. We also show that, like that of the chicken, the Fugu rubripes rpL7a gene possesses only two U36-like sequences within introns 4 and 5. Whereas the two U36 variants in chicken and Fugu possess stretches of complementarity to both 18S and 28S rRNAs, it is noted that only one mammalian variant (U36b) possesses both. Unusually, the stretch of complementarity to 18S rRNA in the mammalian U36a variants and the stretch of complementarity to 28S rRNA in the mammalian U36c variants are not present, appearing to have diverged extensively from their consensus sequence. Additionally, the mammalian U36 variants show a unique heterogeneity in their potential to form a terminal stembox structure predicted for many other box C/D-containing antisense snoRNAs. Finally, the Saccharomyces cerevisiae small nuclear RNA, snR47, is shown to be homologous to the vertebrate U36 snoRNA.

Animals↗

PubMed1998

A new allele of interferon-alpha17 gene encoding IFN-alpha17b is the major variant in human population.

Thirteen interferon (IFN)-alpha functional genes have been reported. Among these, a number of genes have allelic members (variants). In the case of IFN-alpha17, five variants, IFN-alpha17a, IFN-alpha17b, IFN-alpha17c, IFN-alpha17d, and IFN-alphaT, are known. The variants differ from each other by base changes in the coding region, leading to differences in amino acid sequences. We have developed oligonucleotide primers for amplification of IFN-alpha17 gene(s) using polymerase chain reaction (PCR). Genomic DNA, obtained from over 28,000 normal healthy individuals and from four cell lines, were used as templates in PCR to amplify the IFN-alpha17 gene sequences. The resulting PCR products were analyzed by restriction endonuclease digestion and DNA sequencing to identify the presence of variant sequences. The results show that a new variant of IFN-alpha17 is abundantly present (approximately 70%) along with another variant, possibly IFN-alpha17c (approximately 30%), in the genomic DNA of the population examined. This new variant, the protein product of which is identical to IFN-alpha17b, differs from the gene for IFN-alpha17b by a point mutation. We have named it IFN-alpha17b', which is the only variant found in U-937, KG-1, and EB-3 cell lines. Namalwa cells have IFN-alpha17b' and, possibly, IFN-alpha17c in equal proportions.

Alleles↗

PubMed2006

HPV16 variants in squamous intraepithelial lesions in human immunodeficiency virus-negative and -positive Brazilian women.

Emerging evidence supports the role of human papillomavirus (HPV) intratype variations in the development of cervical lesions in immunocompetent women, but few studies investigated HPV16 variants in human immunodeficiency virus (HIV)-positive women. This is the first study in Brazil evaluating HPV16 variants in women with (n = 19) and without (n = 22) HIV infection, as well as cervical lesions. Although non-European variants presented an almost 3-fold increase (13.6% vs. 36.8%) among HIV-positive women, associations between HPV16 variants and HIV infection did not reach statistical significance (Fisher's exact test, p = 0.15). No associations were found between non-European variants and HSIL (Fisher's exact test, p = 0.41), although a significant association was observed between European variants and HSIL among HIV-negative women (Fisher's exact test, p = 0.01). In conclusion, in HIV-negative women the HPV16 European variants seem to influence the occurrence of HSIL, whereas in HIV-positive women, similar roles are atributted to both variants.

Adolescent↗

PubMed1999

Catalytic properties of polymorphic human cytochrome P450 1B1 variants.

Four polymorphic human cytochrome P450 (CYP) 1B1 allelic variants, namely Arg48,Ala119,Leu432,Asn453, Arg48,Ser119,Leu432,Asn453, Arg48, Ala119,Val432,Asn-453 and Arg48,Ser119,Val432,Asn453, were expressed in Escherichia coli together with human NADPH-P450 reductase and the recombinant proteins (in bacterial membranes) were used to assess whether CYP1B1 polymorphisms affect catalytic activities towards a variety of P450 substrates, including diverse procarcinogens and steroid hormones. Activities for activation of 19 procarcinogens to DNA-damaging products by these four CYP1B1 variants in a Salmonella typhimurium NM2009 umu response system were found to be essentially similar, except that a Arg48, Ser119,Leu432,Asn453 variant was slightly more active (1.2- to 1.5-fold) than the other three CYP1B1 enzymes in catalyzing activation of (+)- and (-)-benzo[a]pyrene-7, 8-diols, 7,12-dimethylbenz[a]anthracene-3,4-diol, benzo[g]chrysene-11,12-diol, benzo[b]fluoranthene-9,10-diol, 2-amino-3,5-dimethylimidazo[4,5-f]quinoline, 2-amino-3-methylimidazo[4,5-f]quinoline and 2-aminofluorene. Kinetic analysis of 17beta-estradiol hydroxylation showed that V(max) values for 4-hydroxylation ranged between 0.9 and 1.5 nmol/min/nmol P450 for 4-hydroxylation and 0.3 and 0.6 nmol/min/nmol P450 for 2-hydroxylation in these CYP1B1 variants, with K(m) values ranging from 1 to 9 microM. Interestingly, the ratio of product formation of 4-hydroxyestradiol to 2-hydroxyestradiol was higher for the Val432 variants of CYP1B1 variants than the Leu432 variants of the enzyme. The same trend was noted in the ratio of estrone 4-hydroxylation to estrone 2-hydroxylation catalyzed by CYP1B1 variants. Mutation in the CYP1B1 genes also affected the K(m) and V(max) values in the 6beta-hydroxylation of testosterone and 6beta- and 16alpha-hydroxylation of progesterone. These results indicate that the polymorphisms in the human CYP1B1 gene cause some alterations in catalytic function towards procarcinogens and steroid hormones and thus may make some contribution to susceptibilities of individuals towards mammary and lung cancers in humans.

Alleles↗

PubMed2004

Specific combinations of DNA repair gene variants and increased risk for non-small cell lung cancer.

Several polymorphisms in DNA repair genes have been reported to be associated with lung cancer risk including XPA (-4G/A), XPD (Lys751Gln and Asp312Asn), XRCC1 (Arg399Gln), APE1 (Asp148Glu) and XRCC3 (Thr241Met). As there is little information on the combined effects of these variants, polymorphisms were analyzed in a case-control study including 463 lung cancer cases [among them 204 adenocarcinoma and 212 squamous cell carcinoma (SCC)] and 460 tumor-free hospital controls. Odds ratios (OR) adjusted for age, gender, smoking and occupational exposure were calculated for the variants alone and combinations thereof. For homozygous individuals carrying the Glu variant of APE1, a protective effect was found (OR = 0.77, CI = 0.51-1.16). Individuals homozygous for the variants XPA (-4A) (OR = 1.53, CI = 0.94-2.5), XPD 751Gln (OR = 1.39, CI = 0.90-2.14) or XRCC3 241Met (OR = 1.29, CI = 0.85-1.98) showed a slightly higher risk for lung cancer overall. In the subgroup of adenocarcinoma cases, adjusted ORs were increased for individuals homozygous for XPA (-4A) (OR = 1.62, CI = 0.91-2.88) and XRCC3 241Met (OR = 1.65; CI = 0.99-2.75). When analyzing the combined effects of variant alleles, 54 patients and controls were identified that were homozygous for two or three of the potential risk alleles [i.e. the variants in nucleotide excision repair, XPA (-4A) and XPD 751Gln, and in homologous recombination, XRCC3-241Met]. ORs were significantly increased when all patients (OR = 2.37; CI = 1.26-4.48), patients with SCC (OR = 2.83; CI = 1.17-6.85) and with adenocarcinoma (OR = 3.05; CI = 1.49-6.23) were analyzed. Combinations of polymorphisms in genes involved in the same repair pathway (XPA + XPD or XRCC1 + APE1) affected lung cancer risk only in patients with SCC. These results indicate that lung cancer risk is only moderately increased by single DNA repair gene variants investigated but it is considerably enhanced by specific combinations of variant alleles. Analyses of additional DNA repair gene interactions in larger population-based studies are warranted for identification of high-risk subjects.

Adenocarcinoma↗

PubMed1996

Amino acid polymorphism and rare electrophoretic variants of G6PD from natural populations of Drosophila melanogaster.

Identifying the amino acid changes responsible for electrophoretic variants is essential to understanding the significance of allozyme polymorphism in adaptation. The amino acid mutations responsible for the common G6PD allozyme polymorphisms in Drosophila melanogaster have been recently described. This study characterizes the amino acid changes associated with 11 rare electrophoretic G6PD variants. The 11 rare electrophoretic variants result from six independent amino acid mutations. The in vivo function of the rare variants was determined in an earlier study and most variants fell into one of two function classes. It is shown here that the function of the rare variants reflects the state of the Pro/Leu mutation responsible for the A/B allozyme polymorphism in each variant. Two mutations destabilize quaternary structure resulting in shifts from tetrameric dimeric alleles, and one of these also results in a variant with in vivo function intermediate to A and B. That mutation is an aspartic-acid-to-asparagine change that is two residues away from the Pro/Leu polymorphism responsible for the A/B dimertetramer quaternary shift. Structure-function relationships based on studies of human G6PD deficiency-associated mutations predict that these last two amino acid changes fall within the protein domain responsible for NADP binding.

Amino Acid Sequence↗

PubMed2003

Destabilizing interactions among [PSI(+)] and [PIN(+)] yeast prion variants.

The yeast Sup35 and Rnq1 proteins can exist in either the noninfectious soluble forms, [psi-] or [pin-], respectively, or the multiple infectious amyloid-like forms called [PSI+] or [PIN+] prion variants (or prion strains). It was previously shown that [PSI+] and [PIN+] prions enhance one another's de novo appearance. Here we show that specific prion variants of [PSI+] and [PIN+] disrupt each other's stable inheritance. Acquiring [PSI+] often impedes the inheritance of particular [PIN+] variants. Conversely, the presence of some [PIN+] variants impairs the inheritance of weak [PSI+] but not strong [PSI+] variants. These same [PIN+] variants generate a single-dot fluorescence pattern when a fusion of Rnq1 and green fluorescent protein is expressed. Another [PIN+] variant, which forms a distinctly different multiple-dot fluorescence pattern, does not impair [PSI+] inheritance. Thus, destabilization of prions by heterologous prions depends upon the variants involved. These findings may have implications for understanding interactions among other amyloid-forming proteins, including those associated with certain human diseases.

Gene Expression Regulation, Fungal↗

PubMed2005

Haplotypes produced from rare variants in the promoter and coding regions of angiotensinogen contribute to variation in angiotensinogen levels.

The most efficient study design to map genes underlying complex traits will be determined by assumptions about whether the genetic effects are likely to be due to relatively few common variants or multiple rare variants. To examine the possibility that rare variants may influence blood pressure, we sequenced a 6.8 kb region of the angiotensinogen (AGT) gene in 29 male Nigerians with high plasma AGT levels and 28 with low levels. The frequency of haplotypes produced from rare variants in the promoter and coding regions was significantly different between the two groups, and it is unlikely that this difference was due to the manner in which the rare variants were selected. Further analysis suggested that most of the haplotypes produced by these rare variants are found on a haplotype background created by three common SNPs. Our study confirms in an additional trait that rare variants can influence the distribution of complex traits; whether these variants can be captured by common SNPs or haplotypes requires further investigation.

Angiotensinogen↗

PubMed1995

Analysis of human papillomavirus type 16 variants indicates establishment of persistent infection.

Sequence differences in the noncoding region of the human papillomavirus type 16 (HPV-16) genome were displayed using single-stranded conformational polymorphism (SSCP) analysis of polymerase chain reaction (PCR)-amplified material. Two variants accounted for 50%-70% of all HPV-16 variants from 3 cohorts in Seattle. Seventy subjects who were repeatedly HPV-16 DNA-positive over 2-8 4-monthly visits showed an identical SSCP pattern at every visit. Only 10%-20% of the specimens showed evidence of infection by multiple variants when assessed by SSCP. However, cloning and sequencing of the PCR products revealed a substantially higher proportion of specimens with > 1 variant. Sequencing many clones from each specimen confirmed that 1 major variant seemed to predominate over time, whereas minor variants appeared more transient. These results suggest that HPV-16 establishes a persistent infection in which a single variant predominates: coinfection with addition HPV-16 variants results in a minor population of HPV-16 genomes.

Base Sequence↗

PubMed2026

Frequency and clinical features of germline pathogenic variants in sarcoma: a case-control study.

BACKGROUND: Germline multigene panel testing is not yet integrated into standard care for patients with sarcoma. This study aimed to assess the frequency and distribution of germline pathogenic variants in patients with sarcoma compared with cancer-free controls and identify differences between patients with and without germline pathogenic variants. METHODS: This retrospective cohort included 488 sarcoma patients and 2440 cancer-free controls matched 1:5 by age, sex, and ethnicity. Multigene panel testing was performed between 2016 and 2024 at a single germline testing laboratory. The frequency of germline pathogenic variants in selected genes was compared using Fisher exact test with odds ratios (ORs) and 95% confidence intervals. Additionally, within the case-only cohort, clinical characteristics were evaluated to assess associations with the presence of germline pathogenic variants in any gene. RESULTS: Among 488 patients with sarcoma, 67.8% (n = 331) were female, with a median age at sarcoma diagnosis of 47 years (range = 0.5-87.5 years). Cases had a higher frequency of germline pathogenic variants compared with controls (26.2% vs 10.5%; OR = 3.05, P < .001). We observed a higher frequency of germline pathogenic variants in TP53, BRCA2, CHEK2, NF1, SDHA, BRIP1, POT1, RB1, and CDH1 among patients with sarcoma compared with controls. Age at sarcoma diagnosis did not differ between groups. CONCLUSIONS: This study confirms the high detection rate of germline pathogenic variants in patients with sarcoma and describes several associated genes. These findings indicate that age at sarcoma diagnosis may not reliably predict germline pathogenic variants. Expanding germline testing for patients with sarcoma would enhance personalized treatment strategies and familial risk assessment.

Humans↗

PubMed1998

Expression of oestrogen receptor-alpha splicing variants and oestrogen receptor-beta in endometrium of infertile patients.

Endometrium is one of the main target tissues of oestrogens. Although homozygous inactivation of oestrogen receptor-alpha leads to infertility in transgenic mice, oestrogen receptor-alpha is detected in endometrium of patients with unexplained infertility. Oestrogen receptor-alpha splicing variants and oestrogen receptor-beta have been studied in oestrogen target tissues, but their expression in endometrium throughout the menstrual cycle and in unexplained infertility is unknown. Using reverse transcription-polymerase chain reaction (RT-PCR), we studied the expression of oestrogen receptor-alpha splicing variants and oestrogen receptor-beta in uterine biopsies from 12 patients with endometriosis and 15 patients with unexplained infertility. A control group included 19 women who had had a previous pregnancy. Our study gave evidence of exon 2, 3, 4 or 7 deleted oestrogen receptor-alpha variants co-existing with the wild-type receptor. We did not find any exon 5 or 6-deleted variants. Exon 4 or 7-deleted variants were detected in all samples. Exon 2 or 3-deleted variants were detected at a similar frequency in fertile women (58 and 68% respectively), endometriotic patients (67 and 83% respectively) and infertile patients (73 and 80% respectively). During the follicular phase, there was a non-significant trend towards a lower frequency of exon-2 deleted variants in the fertile group when compared with the hypofertile group. Oestrogen receptor-beta was detected in all samples. Our preliminary study showed that altered expression of oestrogen receptor-alpha variants and oestrogen receptor-beta may not explain the hypofertility state.

Alternative Splicing↗

PubMed2006

Antigenomic delta ribozyme variants with mutations in the catalytic core obtained by the in vitro selection method.

We have used the in vitro selection method to search for catalytically active variants of the antigenomic delta ribozyme with mutations in the regions that constitute the ribozyme active site: L3, J1/4 and J4/2. In the initial combinatorial library 16 nt positions were randomized and the library contained a full representation of all possible sequences. Following ten cycles of selection-amplification several catalytically active ribozyme variants were identified. It turned out that one-third of the variants contained only single mutation G80U and their activity was similar to that of the wild-type ribozyme. Unexpectedly, in the next one-third of the variants the C76 residue, which was proposed to play a crucial role in the ribozyme cleavage mechanism, was mutated. In these variants, however, a cytosine residue was present in a neighboring position to the polynucleotide chain. It shows that the ribozyme catalytic core possesses substantial 'structural plasticity' and the capacity of functional adaptation. Four selected ribozyme variants were subjected to more detailed analysis. It turned out that the variants differed in their relative preferences towards Mg2+, Ca2+ and Mn2+ ions. Thus, the functional properties of the variants were dependent on both the structure of their catalytic sites and divalent metal ions performing catalysis.

Base Sequence↗

PubMed1989

Tissue-type plasminogen activator variants with domain duplications and rearrangements.

The interactions between tPA domains that are important for catalysis are poorly understood. We have probed the function of interdomain interactions by generating tPA variants in which domains are duplicated or rearranged. The proteins were expressed in a transient mammalian expression system and tested in vitro for their ability to activate plasminogen, induce fibrinolysis and bind to a forming fibrin clot. Duplication of the heavy chain domains of tPA produced enzymatically active tPA variants, many of which demonstrated similar in vitro amidolytic and fibrinolytic activity and similar fibrin affinity to the parent molecule. Zymographic analysis of the domain duplication tPA variants showed one major active species for each variant. Selection of the residues duplicated and the interdomain spacing were found to be critical considerations in the design of tPA variants with duplicated domains. We also rearranged the domains of tPA such that kringle 1 replaced the second kringle domain and vice versa. An analysis of these variants indicates that the first kringle domain can confer fibrin affinity to a tPA variant and function in place of kringle 2. Therefore, in wild-type tPA, the functions of kringle 1 and kringle 2 must be dependent partially on their orientation within the heavy chain of the protein. The functional autonomy of the heavy and light chains of tPA is demonstrated by the activity of a tPA variant in which the order of the heavy and light chains was reversed.

Base Sequence↗

PubMed2005

Influence of an insertion variant in the 5'UTR of the endothelin-1 gene on orthostatic intolerance.

BACKGROUND: Orthostatic intolerance is a multifactorial disease in which the genetic contribution is probably the result of a number of genes acting in combination. Recent work has shown that orthostatic intolerance is influenced by endothelial nitric oxide synthase gene polymorphisms. Since endothelin-1 (ET-1) is one of the most important vasoconstrictor peptides, a frequent adenine insertion polymorphism within the 5'-untranslated region (5'UTR), which is of functional importance for ET-1 expression, could influence orthostatic intolerance. The aim of this study was therefore to ascertain whether this frequent variant of the endothelin-1 gene influences the risk for orthostatic intolerance. METHODS: We studied 257 white patients (120 cases with orthostatic intolerance and 137 controls) for genotyping of the 5'UTR I variant. From this cohort, 111 patients and 99 control subjects underwent a tilt-table test or an upright posture study, including monitoring of blood pressure, heart rate, and plasma catecholamines, in the supine position and during 30 minutes of standing. Genotyping was performed in all participants. Chi tests of independence were used to test for associations between orthostatic intolerance and genotype. In addition, an association of the insertion polymorphism with hemodynamic variables (heart rate, supine and upright blood pressure) was ascertained using one-way analysis of variance. RESULTS: The 5'UTR I variant was significantly less common in patients with orthostatic intolerance (allele frequency 0.36 and 0.28, in controls and cases, respectively). Additionally, we found a significant decrease in the risk of orthostatic intolerance among people who were homozygous for the 5'UTR variant (I/I) compared with the wild-type variant (D/D) (odds ratio, 0.41; 95% confidence interval, 0.17 to 0.97; P = 0.04). No association between the 5'UTR variant and heart rate or blood pressure regardless of diagnosis was found. CONCLUSIONS: Our current results suggest that the hereditary adenine insertion variant in the 5'-UTR of the endothelin-1 gene is protective for orthostatic intolerance. The increased ET-1 protein expression that has been linked with the I variant might be associated with a more efficient hemodynamic response to standing. This is likely one of several common genetic loci that may represent modifiers of orthostatic intolerance phenotypes.

5' Untranslated Regions↗

PubMed1998

T235 variant of the angiotensinogen gene and blood pressure in the Chilean population.

BACKGROUND: The angiotensinogen gene has recently been linked to essential hypertension. A variant within this gene, encoding threonine rather than methionine at amino acid position 235, was associated with essential hypertension. However, results of new studies have not confirmed this association, suggesting that ethnic differences may explain the different results. OBJECTIVE: To evaluate whether the T235 variant is associated with a higher incidence of essential hypertension among Hispanics (a group that has scarcely been evaluated) and to determine whether T235 is associated with variations in the plasma renin activity or the serum aldosterone level. PATIENTS AND METHOD: We studied 64 patients with essential hypertension and 62 normotensives, matched for age and sex. We obtained samples for determinations of plasma renin activity, serum aldosterone level and genome DNA from all subjects. The genomic DNA was amplified using the polymerase chain reaction technique and digested by the restriction enzyme streptococcus faecalis (Sfa NI) which cuts M235 only, not T235. RESULTS: The patients with essential hypertension had a higher prevalence of the risk variant T235 (alleles 77/128 = 60.2%) than did the normotensive controls (alleles 65/124 = 52.4%), but the difference was not statistically significant (chi2=1.53, P=0.22). The plasma renin activity levels in hypertensives were not statistically different for homozygous T235, heterozygous and homozygous M235 (1.0 +/- 0.96, 2.0 +/- 2.25 and 1.55 +/- 1.49 ng/ml per h, respectively, P=0.5 1). However, when we considered those hypertensives with low plasma renin activity levels (< 1 ng/ml per h), we found a high prevalence (72.7%) of subjects homozygous for the T235 variant. We found no association between the T235 variant and the serum aldosterone levels in hypertensive and normotensive subjects. CONCLUSIONS: We demonstrated that there is a high prevalence of T235 variant in our Hispanic population. The slight difference between prevalences of T235 variant among hypertensive and normotensive subjects that we found was not statistically significant and did not permit us to establish an association between T235 variant and essential hypertension. We believe that only studying a larger cohort of subjects could show whether there is a quantitative effect of the T allele on plasma renin activity levels.

Aldosterone↗

PubMed1992

Guinea pig or rabbit lung flavin-containing monooxygenases with distinct mobilities in SDS-PAGE are allelic variants that differ at only two positions.

Both guinea pig and rabbit express two variants of the 'lung' flavin-containing monooxygenase (FMO), observed as three distinct phenotypes based on mobility differences in SDS-PAGE. Samples of messenger RNA prepared from lungs of the two homozygous phenotypes of the guinea pig were used for the construction of two cDNA libraries. The libraries were screened with a cDNA encoding the rabbit lung FMO, and positive clones for each guinea pig lung FMO variant were isolated and sequenced. A full length clone from each library was found to encode a protein of 535 amino acids containing two pyrophosphate binding sites. Comparison of the sequences of the guinea pig and rabbit lung FMOs shows that their primary structures are 86% identical. The coding region sequences of the guinea pig variants differ at only two positions, and both differences result in amino acid substitutions. Sequence analysis has also been completed on a partially characterized variant of the rabbit lung FMO. As with the guinea pig, the nucleotide and amino acid sequences of the rabbit variants differ at only two positions. The cDNAs encoding the guinea pig variants were expressed in yeast. The activities of the enzymes are characteristic of the lung FMO, and the mobilities of the expressed enzymes are the same as those observed for the variants present in guinea pig pulmonary microsomal preparations. Similar to findings for the rabbit, analysis of genomic DNA indicates that the guinea pig lung FMO is associated with a single gene. The results of cDNA sequence analysis, expression in yeast, and analysis of genomic DNA indicate that the multiple lung FMOs in guinea pig and rabbit are allelic variants whose mobilities in SDS-PAGE are markedly altered by minimal changes in primary structure.

Alleles↗