Adult onset Still's disease: response to Enbrel.
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Adult↗
Biomedical subjects
L Pascoe
Publications and source records attributed to L Pascoe.
Angiotensin-converting enzyme and angiotensinogen gene polymorphisms are non-randomly distributed in oral contraceptive-induced hypertension.
OBJECTIVES AND METHODS: Oral contraceptives (OC) usage increases serum angiotensinogen levels to three to five times normal and about 5% of these women develop arterial hypertension. The genetic contribution to this susceptibility to OC-induced hypertension is poorly understood. We have analyzed the genotypes of 149 hypertensive and 101 normotensive women using oral contraceptives, for three genetic polymorphisms in genes of the renin-angiotensin system: an insertion/deletion (I/ D) in the angiotensin converting enzyme (ACE) gene, the T235M polymorphism of the angiotensinogen gene (AGT) and a point mutation in its promoter. RESULTS: After cessation of oral contraception the mean arterial pressures of the hypertensive women were separable into two non-overlapping groups; 88 of the women remained hypertensive and 61 returned to normal blood pressure. Both groups of hypertensive women had a similarly higher frequency of hypertensive relatives than the normotensive women, but were otherwise similar. The 235T allele of AGT was significantly increased in frequency in the 61 oral contraceptive-inducible hypertensive women compared with the controls and the 88 women that remained hypertensive. The ACE I/D genotypes were similarly distributed within the three groups of women, but were distinctly non-random in the oral contraceptive-induced hypertensive women when they were also classified by AGT genotype. CONCLUSION: This statistical interaction of genotype frequencies suggests that the genetic basis of susceptibility to OC-induced hypertension is complex.
Adult↗
Deletion hybrid genes, due to unequal crossing over between CYP11B1 (11beta-hydroxylase) and CYP11B2(aldosterone synthase) cause steroid 11beta-hydroxylase deficiency and congenital adrenal hyperplasia.
Chromosomal rearrangements are natural experiments that can provide unique insights into in vivo regulation of genes and physiological systems. We have studied a patient with congenital adrenal hyperplasia and steroid 11beta-hydroxylase deficiency who was homozygous for a deletion of the CYP11B1 and CYP11B2 genes normally required for cortisol and aldosterone synthesis, respectively. The genes were deleted by unequal recombination between the tandemly arranged CYP11B genes during a previous meiosis, leaving a single hybrid gene consisting of the promoter and exons 1-6 of CYP11B2 and exons 7-9 of CYP11B1. The hybrid gene also carried an I339T mutation formed by intracodon recombination at the chromosomal breakpoint. The mutant complementary DNA corresponding to this gene was expressed in COS-1 cells and was found to have relatively unimpaired 11beta-hydroxylase and aldosterone synthase activities. Apparently the 11beta-hydroxylase deficiency and the adrenal hyperplasia are due to the lack of expression of this gene in the adrenal zona fasciculata/reticularis resulting from replacement of the CYP11B1 promoter and regulatory sequences by those of CYP11B2.
Adrenal Hyperplasia, Congenital↗
The use of botulinum toxin-A in the treatment of patients with fibromyalgia.
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Botulinum Toxins, Type A↗
The efficiency of genetic analysis of DNA from aged siblings to detect chromosomal regions implicated in longevity.
Studies of the frequencies of different alleles in young adults and aged individuals have implicated several genes, such as ApoE and ACE, in longevity. However such association studies can easily give rise to spurious results through unsuspected population subdivision, and an approach making use of genetic relationships among relatives is desirable. We have studied the effectiveness of non-parametric genetic analysis to detect different types of loci affecting longevity. The non-parametric method has high statistical power to detect infrequent recessive alleles that are required for, or significantly increase the probability of, survival to advanced age. Statistical power is reduced if a proportion of carriers of the alternative allele is allowed to survive. The method is least effective in detecting alleles that occur at low frequency in young individuals and that subsequently experience high mortality, as is the case for carriers of the epsilon4 allele of ApoE. Genotyping errors will also reduce the value of the NPL statistic in a linear fashion with the error rate and the number of loci genotyped. We have also used the method to analyse genotypes of seven highly polymorphic markers near the ApoE gene in a sample of 188 sibships of nonagenarians and centenarians (n=434) and their children (n=124), however no excess sharing of alleles was detected.
Adult↗
CYP11B2 gene polymorphisms in idiopathic hyperaldosteronism.
Primary aldosteronism is characterized by autonomous production of aldosterone and arterial hypertension, and it occurs in 2 principal forms: aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). APA can be cured through removal of the adenoma, whereas IHA leads to hypertension that must be treated with medication. The origin of the autonomous aldosterone production in IHA is poorly understood, but genetic factors may contribute to its cause. To test the hypothesis that variants of the aldosterone synthase gene may contribute to susceptibility to IHA, we compared genotypes at 3 polymorphic sites in the CYP11B2 gene in patients with IHA (n=90) with those found in patients with APA (n=38), in patients with essential hypertension (n=72), and in normotensive individuals (n=102). We observed significant linkage disequilibrium among the 3 polymorphisms with 2 frequent haplotypes in all groups studied. One haplotype (C2R) was found to be increased in frequency in the IHA group (47%) compared with the other groups, which had a similar haplotype frequency (36%). The 3 polymorphisms studied have been implicated in either essential hypertension or excess aldosterone production in previous studies. Because of the strong linkage disequilibrium, the observed results could be due to the action of any 1 of the 3 alleles or to another allele in linkage disequilibrium with them. Our results suggest that variations in the CYP11B2 gene may contribute to dysregulation of aldosterone synthesis and lead to susceptibility to IHA.
Alleles↗
Sequence similarities between a novel putative G protein-coupled receptor and Na+/Ca2+ exchangers define a cation binding domain.
cDNA clones encoding a novel putative G protein-coupled receptor have been characterized. The receptor is widely expressed in normal solid tissues. Consisting of 1967 amino acid residues, this receptor is one of the largest known and is therefore referred to as a very large G protein-coupled receptor, or VLGR1. It is most closely related to the secretin family of G protein-coupled receptors based on similarity of the sequences of its transmembrane segments. As demonstrated by cell surface labeling with a biotin derivative, the recombinant protein is expressed on the surface of transfected mammalian cells. Whereas several other recently described receptors in this family also have large extracellular domains, the large extracellular domain of VLGR1 has a unique structure. It has nine imperfectly repeated units that are rich in acidic residues and are spaced at intervals of approximately 120 amino acid residues. These repeats resemble the regulatory domains of Na+/Ca2+ exchangers as well as a component of an extracellular aggregation factor of marine sponges. Bacterial fusion proteins containing two or four repeats specifically bind 45Ca in overlay experiments; binding is competed poorly by Mg2+ but competed well by neomycin, Al3+, and Gd3+. These results define a consensus cation binding motif employed in several widely divergent types of proteins. The ligand for VLGR1, its function, and the signaling pathway(s) it employs remain to be defined.
Adrenal Glands↗
Genetic, biochemical, and clinical studies of patients with A328V or R213C mutations in 11betaHSD2 causing apparent mineralocorticoid excess.
Apparent mineralocorticoid excess is a recessively inherited hypertensive syndrome caused by mutations in the 11beta-hydroxysteroid dehydrogenase type 2 gene, which encodes the enzyme normally responsible for converting cortisol to inactive cortisone. Failure to convert cortisol to cortisone in mineralocorticoid-sensitive tissues permits cortisol to bind to and activate mineralocorticoid receptors, causing hypervolemic hypertension. Typically, these patients have increased ratios of cortisol to cortisone and of 5alpha- to 5beta-cortisol metabolites in serum and urine. We have studied 3 patients in 2 families with severe, apparent mineralocorticoid excess and other family members in terms of their genetic, biochemical, and clinical parameters, as well as normal controls. Two brothers were homozygous for an A328V mutation and the third patient was homozygous for an R213C mutation in the 11beta-hydroxysteroid dehydrogenase type 2 gene; both mutations caused a marked reduction in the activity of the encoded enzymes in transfection assays. The steroid profiles of the 7 heterozygotes and 2 other family members studied were completely normal. The results of a novel assay used to distinguish 5alpha- and 5beta-tetrahydrometabolites suggest that 5beta-reductase activity is reduced or inhibited in apparent mineralocorticoid excess. In 1 patient undergoing renal dialysis for chronic renal insufficiency, direct control of salt and water balance completely corrected the hypertension, emphasizing the importance of mineralocorticoid action in this syndrome.
11-beta-Hydroxysteroid Dehydrogenases↗
Prenatal diagnosis and treatment of 11beta-hydroxylase deficiency congenital adrenal hyperplasia resulting in normal female genitalia.
Congenital adrenal hyperplasia (CAH) consists of autosomal recessive disorders of cortisol biosynthesis, which in the majority of cases result from 21-hydroxylase deficiency. Another enzymatic defect causing CAH is 11beta-hydroxylase deficiency. In both forms, the resulting excessive androgen secretion causes genital virilization of the female fetus. For over 10 yr female fetuses affected with 21-hydroxylase deficiency have been safely and successfully prenatally treated with dexamethasone. We report here the first successful prenatal treatment with dexamethasone of an affected female with 11beta-hydroxylase deficiency CAH. The family had two girls affected with 1beta-hydroxylase deficiency born with severe ambiguous genitalia who were both homozygous for the T318M mutation in the CYP11B1 gene, which codes for the 11beta-hydroxylase enzyme. In the third pregnancy in this family, the female fetus was treated in utero by administering dexamethasone to the mother, starting at 5 weeks gestation. The treatment was successful, as the newborn was not virilized and had normal female external genitalia. A second family with two affected sons was also studied in preparation for a future pregnancy. We report a novel 1-bp deletion in codon 394 (R394delta1) in the CYP11B1 gene in this family.
Adrenal Hyperplasia, Congenital↗
Structural analysis and evaluation of the 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) gene in human essential hypertension.
AIM: Mutations of the 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) gene cause the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive form of hypertension. We therefore investigated the question of whether variants of the 11beta-HSD2 gene can contribute to genetic susceptibility to essential hypertension. SUBJECTS AND METHODS: We performed a linkage study in 162 French hypertensive sibships using the affected sib-pair method on 347 sibling pairs and a polymorphic microsatellite marker that we identified in a 30 kb cosmid clone containing the 11beta-HSD2 gene. The coding sequence, introns 2-4 and 350 bp of the 5'-flanking region of the 11beta-HSD2 gene were screened for polymorphisms by polymerase chain reaction/single-strand conformation polymorphism, and a single polymorphism, Glu178/Glu (G534A), was identified in exon 3, which did not change the encoded amino acid sequence. A case-control study was conducted on 370 hypertensive subjects with a positive family history of hypertension and 783 French subjects with hypertension with or without a family history of hypertension, compared with 313 normotensive control subjects, all of whom were analyzed for the newly identified bi-allelic polymorphism. RESULTS: Statistical analyses using the affected sib-pair method did not show significant linkage between the 11beta-HSD2 microsatellite marker and hypertension. Furthermore, no positive association with hypertension was found with the Glu178/Glu (G534A) polymorphism. CONCLUSION: Our data do not suggest that variants of the 11beta-HSD2 gene contribute substantially to essential hypertension in Caucasians.
11-beta-Hydroxysteroid Dehydrogenases↗
Structural analysis and evaluation of the aldosterone synthase gene in hypertension.
Anomalies in either of the tightly linked genes encoding the enzymes CYP11B1 (11beta-hydroxylase) or CYP11B2 (aldosterone synthase) can lead to important changes in arterial pressure and are responsible for several monogenically inherited forms of hypertension. Mutations in these genes or their regulatory regions could thus contribute to genetic variation in susceptibility to essential hypertension. To test this hypothesis, we performed 2 complementary studies of the CYP11B1/CYP11B2 locus in essential hypertension. After characterizing a DNA contig containing the CYP11B1 gene and mapping the gene in the Centre d'Etudes du Polymorphisme Humain reference panel of families, we performed a linkage study with 292 hypertensive sibling pairs and a highly informative microsatellite marker near CYP11B1. We also analyzed the association of 2 frequent biallelic polymorphisms of the CYP11B2 gene, 1 in the promoter at position -344 (-344C/T) and the other, a common gene conversion in intron 2, with hypertension in 380 hypertensive patients and 293 normotensive individuals. Statistical analyses did not show significant linkage of the CYP11B1 microsatellite marker to hypertension. No positive association with hypertension was found with the gene conversion in intron 2, but a positive association with hypertension was found with the -344T allele. The hypertensive and normotensive samples differed significantly in both genotype (P=0.023) and allele frequencies (P=0.010). Our data suggest a modest contribution of the CYP11B2 gene to essential hypertension.
Adult↗
Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol.
CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) are 93% identical mitochondrial enzymes that both catalyze 11beta-hydroxylation of steroid hormones. CYP11B2 has the additional 18-hydroxylase and 18-oxidase activities required for conversion of 11-deoxycorticosterone to aldosterone. These two additional C18 conversions can be catalyzed by CYP11B1 if serine-288 and valine-320 are replaced by the corresponding CYP11B2 residues, glycine and alanine. Here we show that such a hybrid enzyme also catalyzes conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. These latter two steroids are present at elevated levels in individuals with glucocorticoid suppressible hyperaldosteronism (GSH) and some forms of primary aldosteronism. Their production by the recombinant CYP11B enzyme is enhanced by substitution of further amino acids encoded in exons 4, 5, and 6 of CYP11B2. A converted CYP11B1 gene, containing these exons from CYP11B2, would be regulated like CYP11B1, yet encode an enzyme with the activities of CYP11B2, thus causing GSH or essential hypertension. In a sample of 103 low renin hypertensive patients, 218 patients with primary aldosteronism, and 90 normotensive individuals, we found a high level of conversion of CYP11B genes and four cases of GSH caused by unequal crossing over but no gene conversions of the type expected to cause GSH.
Case-Control Studies↗
Isolated aldosterone synthase deficiency caused by simultaneous E198D and V386A mutations in the CYP11B2 gene.
Isolated deficiencies in aldosterone biosynthesis are caused by mutations in the CYP11B2 (aldosterone synthase) gene. Patients with this deficiency have impaired aldosterone synthesis, exhibit increased plasma renin activity, secrete increased amounts of the steroid precursors DOC, corticosterone, and 18OHDOC, and are subject to salt wasting and poor growth. Two forms are generally distinguished. The first, corticosterone methyloxidase type I (CMO I or type 1 deficiency), is characterized by no detectable aldosterone secretion, a low or normal secretion of the steroid 18OHB, and are always found to have mutations that completely inactivate the encoded CYP11B2 enzyme. The second form (CMO II or type 2 deficiency) may have low to normal levels of aldosterone, but at the expense of greatly increased secretion of its immediate precursor 18OHB. These patients usually have a CYP11B2 enzyme with some residual enzymatic activity, especially 11beta-hydroxylase activity. We have studied two twins with an isolated aldosterone synthase activity who have a clinical profile typical of the type 1 deficiency. Their CYP11B2 genes are homozygous for three sequence changes, R173K, E198D, and V386A. In transfection assays these substitutions individually have modest effects on the encoded enzyme, but when found together they result in an enzyme with a decreased 11beta-hydroxylase activity, a large decrease of 18-hydroxylase activity, and no detectable 18-oxidase activity. This residual activity is more typical of that observed in patients classified as having CMO II deficiency, rather than CMO I deficiency, where no activity is detectable. This disparity between the CYP11B2 enzyme with residual activity and a clinical phenotypic typical of the type 1 deficiency, suggests that phenotype genotype relationships are not yet fully understood.
Cytochrome P-450 CYP11B2↗
The amino acid substitutions Ser288Gly and Val320Ala convert the cortisol producing enzyme, CYP11B1, into an aldosterone producing enzyme.
Transfection studies with cDNAs encoding hybrids between the highly similar cytochrome P450 enzymes, CYP11B1 (steroid 11 beta-hydroxylase) and CYP11B2 (aldosterone synthase) have identified which amino acids determine the different activities of the enzymes.
Aldosterone↗
[A case of apparent mineralocorticoid excess caused by type 2 11 beta- hydroxysteroid dehydrogenase deficiency].
The syndrome of apparent mineralocorticoid excess is a recessively inherited form of low renin hypertension. The syndrome is characterised by sodium retention and hypervolemia despite low plasma renin activity and aldosterone levels. Patients with this syndrome have mutations in the 11HSD2 gene which encodes the enzyme which normally converts cortisol in the renal tubule to its inactive form, cortisone. The unconverted cortisol is thus able to bind and activate the mineralocorticoid receptor, displacing its usual ligand, aldosterone, causing the apparent mineralocorticoid excess. We have studied a patient with severe hypertension, low renin and aldosterone, and a chronic hypokalemic alkalosis at age 4. The analysis of cortisone, cortisol and their metabolites showed the specific pattern of the apparent mineralocorticoid excess. In serum and urine, there was a dramatic decrease of cortisone and its metabolite, while cortisol and its metabolites were non affected.
11-beta-Hydroxysteroid Dehydrogenases↗
[Hyperaldosteronism sensitive to dexamethasone with adrenal adenoma. Clinical, biological and genetic study].
OBJECTIVES: Dexamethasone-sensitive hyperaldosteronism is associated with early onset hypertension and primary hyperaldosteronism. Diagnosis is difficult but can be improved by genetic testing for the mutant gene. METHODS: We collected the clinical, biological and genetic elements observed in a family with dexamethasone-sensible hyperaldosteronism. Complete data were obtained in 5 adult subjects with the disease. Degree of hypertension varied, more so in the second generations as did hypokaliaemia and hyperaldosteronism. In affected patients, there was a 10 to 50 fold increase in urinary 18-OH components and 18 oxocortisol. RESULTS: Single dose (1.5 mg) dexamethasone led to a greater than 80% drop in aldosterone levels in the blood and urine, confirming the abnormal effect of ACTH on mineralocorticoid secretion. At the dose of 1 mg/d for 10 weeks, dexamethasone lowered mean 24-H ambulatory arterial pressure (11.8/9.6 mmHg) and corrected for the hypokaliaemia (+0.54 mmol/l) and the hyperaldosteronism (mean decrease -36% and -75% in blood and urine respectively). An adrenal tumour was identified in hyperplasic glands in two subjects and a micronodular formation was identified in two others. The specific molecular diagnosis of the disease was done with Southern blotting. Among the 18 families in 3 generations, 8 carried a 11 beta OHase-aldosterone synthetase chimeric gene. This mutation cosegregates with hormonal abnormalities and confirms the autosomal dominant inheritance of the disease. CONCLUSION: The simplicity and rapidity of genetic testing allows early diagnosis of this disease among families with early onset hypertension and associated hyperaldosteronism with or without adrenal hyperplasia and/or a tumoral formation.
Adolescent↗
Genetic recombination as a cause of inherited disorders of aldosterone and cortisol biosynthesis and a contributor to genetic variation in blood pressure.
CYP11B1 (11 beta-hydroxylase) and CYP11B2 (aldosterone synthase) are steroidogenic enzymes which mediate the final step (11 beta-hydroxylation) in cortisol synthesis and the final three steps (11 beta-hydroxylation, 18-hydroxylation, and 18-oxidation) in aldosterone synthesis, respectively. The enzymes share 93% identity in amino acid sequence and are encoded by two structurally similar genes which are located in tandem on chromosome 8q22, approximately 40 kb apart. Expression of the aldosterone synthase gene (CYP11B2) is limited to the zona glomerulosa of the adrenal cortex, thereby limiting the synthesis of aldosterone to that zone, where it is principally regulated by plasma levels of angiotensin II and potassium. The 11 beta-hydroxylase gene (CYP11B1) is expressed in the zona fasciculata, the zone which also expresses a 17-hydroxylase activity, where it mediates cortisol synthesis under the control of ACTH. Genetic recombination involving a mispairing of the two CYP11B genes can lead to duplications and deletions of the genes, creation of hybrid genes of several forms, or transfer of coding and regulatory sequences from one gene to the other. Since the two genes have related but different activities, are normally expressed in different zones, and respond to different physiological signals, such recombination has the potential to generate a variety of inherited disorders of steroid production. In this paper we review the range of mutations which can occur and the resulting disorders of steroid biosynthesis, and suggest some novel mutations which might be sought in variants of these endocrinological syndromes.
Aldosterone↗
Reduced genetic load revealed by slow inbreeding in Drosophila melanogaster.
The rate of decline in reproductive fitness in populations of Drosophila melanogaster inbred at an initial rate of approximately 1% per generation has been investigated under both competitive and noncompetitive conditions. Breeding population size was variable in the inbred lines with an estimated harmonic mean of 66.7 +/- 2.2. Of the 60 lines maintained without reserves, 75% survived a period of 210 generations of slow inbreeding and were then rapidly inbred by full-sib mating to near-homozygosity. The initial rate of inbreeding was estimated to be 0.96 +/- 0.16% per generation, corresponding to an effective population size of approximately 50. However, the rate of inbreeding declined significantly with time to average only 0.52 +/- 0.08% per generation over the 210 generation period, most likely due to associative overdominance built up by genetic sampling and selection in the small populations. The total inbreeding depression in fitness was estimated to be 87 +/- 3% for competitive ability and 27 +/- 5% for fitness under uncrowded conditions, corresponding to rates of decline of 2.0 +/- 0.3 and 0.32 +/- 0.07%, respectively, per 1% increase in the inbreeding coefficient. The frequency of lethal second chromosomes in the resultant near-homozygous lines was of the order of 5%, lethal free second chromosomes showed a mean viability under both crowded and uncrowded conditions of approximately 95%, and their population cage fitness was 60% that of Cy/+ heterozygotes. It can be concluded that homozygous genotypes from which deleterious genes of major effect have been eliminated during slow inbreeding may show far less depression in reproductive fitness than suggested by earlier studies of wild chromosome homozygotes. The loss in fitness due to homozygosity throughout the entire genome may be as little as 85-90% under competitive conditions, and 25-30% in an optimal environment.
Animals↗