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Biomedical subjects

S Bähring

Publications and source records attributed to S Bähring.

At least 19 recordsLinked to original sources
PubMed2001

Efficient and cost-effective single nucleotide polymorphism detection with different fluorescent applications.

Three methods-5'nuclease assay with TaqMan, minisequencing, and oligonucleotide ligation assay (OLA)-were compared to detectfive single nucleotide polymorphisms (SNPs) in three separate genes. Each method had advantages and disadvantages. The 5' nuclease assay was the fastest and required only a single step. OLA was the most time consuming to optimize, but once running it was the least expensive method. Minisequencing was universal; however, the technique was also the most expensive. All three methods were reliable and highly effective. Investigators must consider their goals in terms of time, sample number, and expense when selecting among these genotyping techniques.

Base Sequence↗
PubMed2000

Association of a uteroglobin polymorphism with rate of progression in patients with IgA nephropathy.

Uteroglobin gene-disrupted mice develop a nephritis very similar to immunoglobulin A (IgA) nephropathy. Megsin codes for a protein overexpressed in mesangium in patients with IgA nephropathy. Both are candidate genes that might have variants associated with an accelerated progression in patients with IgA nephropathy. We performed an association study of patients with IgA nephropathy and matching control subjects to test whether the G38A polymorphism in the uteroglobin gene, the C2093T polymorphism in the megsin gene, or the angiotensin-converting enzyme (ACE) insertion/deletion polymorphism is associated with IgA nephropathy or rate of disease progression in patients with IgA nephropathy. Of 110 patients with IgA nephropathy, 87 patients were followed up for at least 3 years for the progression study. We also studied 104 healthy volunteers. The uteroglobin, megsin, and ACE polymorphisms were not distributed differently in the 110 patients with IgA nephropathy compared with healthy controls; Hardy-Weinberg equilibrium criteria were fulfilled. The GG genotype of the G38A uteroglobin polymorphism was more common in patients with progression (odds ratio [OR], 3.5; P< 0.006) than the AG+AA genotypes. The G allele was also more common (OR, 2.6; P< 0.009) in patients with versus without progression. The 1/serum creatinine over time plot (in deciliters per milligram per day) was sevenfold steeper in GG patients than the other two genotypes (P = 0.08). No significant associations with disease progression were found for the other gene polymorphisms, and a multivariate analysis showed no interactions. We suggest the hypothesis that the uteroglobin gene contains variant(s) with a bearing on progression rate in patients with IgA nephropathy.

Adult↗
PubMed2000

A cholesterol-lowering gene maps to chromosome 13q.

A cholesterol-lowering gene has been postulated from familial hypercholesterolemia (FH) families having heterozygous persons with normal LDL levels and homozygous individuals with LDL levels similar to those in persons with heterozygous FH. We studied such a family with FH that also had members without FH and with lower-than-normal LDL levels. We performed linkage analyses and identified a locus at 13q, defined by markers D13S156 and D13S158. FASTLINK and GENEHUNTER yielded LOD scores >5 and >4, respectively, whereas an affected-sib-pair analysis gave a peak multipoint LOD score of 4.8, corresponding to a P value of 1.26x10-6. A multipoint quantitative-trait-locus (QTL) linkage analysis with maximum-likelihood binomial QTL verified this locus as a QTL for LDL levels. To test the relevance of this QTL in an independent normal population, we studied MZ and DZ twin subjects. An MZ-DZ comparison confirmed genetic variance with regard to lipid concentrations. We then performed an identity-by-descent linkage analysis on the DZ twins, with markers at the 13q locus. We found strong evidence for linkage at this locus with LDL (P<.0002), HDL (P<.004), total cholesterol (P<.0002), and body-mass index (P<.0001). These data provide support for the existence of a new gene influencing lipid concentrations in humans.

Adult↗
PubMed1999

Quantitative trait loci for blood pressure exist near the IGF-1, the Liddle syndrome, the angiotensin II-receptor gene and the renin loci in man.

Blood pressure (BP) is heritable and finding quantitative trait loci that influence BP is an important step in identifying genes responsible for BP regulation. Sixty-six pairs of dizygotic (DZ) twin subjects and their parents were used in a sib-pair analysis to look for linkage of selected candidate genes to the quantitative trait BP. Microsatellite markers were tested in the vicinity of the gene loci for insulin-like growth factor-1 (IGF-1), Liddle syndrome, autosomal-dominant hypertension with brachydactyly, angiotensinogen, angiotensin II type 1 receptor, angiotensin-converting enzyme, renin, and lipoprotein lipase. BP was measured in a standardized manner. Heart size was determined echocardiographically. Significant linkage was found at the IGF-1, Liddle syndrome, and AT1 receptor gene for systolic BP. Linkage for diastolic BP was found at the autosomal-dominant hypertension with brachydactyly locus. Both systolic and diastolic BP were linked to the renin gene locus. The linkage was most consistent for the IGF-1 gene locus and systolic BP. Linkage was also found between the IGF-1 gene locus and posterior cardiac wall thickness, septal thickness, and left ventricular mass index. It is suggested that these quantitative trait loci may be important for the subsequent detection of allelic variants for elevated BP. Furthermore, these results linking the IGF-1 gene locus to both BP and cardiac dimensions underscore the importance of the IGF-1 gene as a candidate gene for cardiovascular disease.

Adult↗
PubMed1998

Families with autosomal dominant brachydactyly type E, short stature, and severe hypertension.

BACKGROUND: Rare, monogenic forms of hypertension may give insight into novel mechanisms relevant to essential hypertension. Autosomal dominant hypertension with brachydactyly has been documented in a single Turkish kindred; the gene was mapped to chromosome 12p. OBJECTIVE: To describe the molecular genetics of additional families with autosomal dominant hypertension and brachydactyly. DESIGN: Case series. SETTING: Tertiary care medical centers. PATIENTS: An 11-member Canadian family and a 7-member U.S. family, neither of Turkish background, with autosomal dominant hypertension and type E brachydactyly. MEASUREMENTS: Clinical evaluation, genotyping, and haplotype analyses. RESULTS: The mode of inheritance, the type E brachydactyly, and the propensity for stroke were consistent with autosomal dominant hypertension with brachydactyly. The same markers on chromosome 12p cosegregated with the phenotype in the families. A haplotype analysis strongly supported the conclusion that these families have a molecular defect in the same gene. CONCLUSIONS: The syndrome of autosomal dominant hypertension and brachydactyly is not confined to patients of Turkish origin. All persons with brachydactyly should have their blood pressure measured, and the syndrome should be considered if hypertension is found.

Chromosomes, Human, Pair 12↗
PubMed1998

Monozygotic twins concordant for Cayler syndrome.

Deletions within chromosome band 22q11.2 are associated with a variety of conditions, although a simple genotype-phenotype correlation has not been established so far. Environmental factors, chance events, or a second hit theory were supported by two observations of monozygotic twins with 22q11.2 deletions and discordant phenotypes [Goodship et al., J Med Genet 1995;32:746-748; Fryer, J Med Genet 1996;33:173]. We present monozygotic twins concordant for 22q11.2 deletion and Cayler syndrome, favoring the view that there exists a predominant genetic determination of the del 22q11.2 phenotype. As these twins are diamniotic and dichorionic, they may offer a more reliable insight in genetic phenotype determination than the other published, probably monochorionic, twins who may have a discordant malformation by twinning itself.

Chromosomes, Human, Pair 22↗
PubMed1998

A cross-over medication trial for patients with autosomal-dominant hypertension with brachydactyly.

We examined a family with autosomal-dominant hypertension and brachydactyly from northeastern Turkey. The hypertension was defined as severe, resulting in stroke before age 50 years, featuring normal renin, aldosterone, and catecholamine responses, and did not appear to be salt-sensitive. The responsible gene resides on chromosome 12p. To determine which medications were most effective, we performed a prospective clinical trial. We studied 13 affected individuals in a randomized double-blind, cross-over trial including a beta-blocker (BBL), alpha-blocker (ABL), calcium channel blocker (CCB), converting enzyme inhibitor (CEI), and hydrochlorothiazide (HCT) and placebo (PLA). We then added moxonidine (MOX) and continued the trial for an additional period in a single-blind fashion. Each drug was given for four weeks with an option to double the dose after two weeks; each washout period comprised two weeks. Blood, 24-hour urine, and saliva were studied at the outset, and blood and urine samples were obtained at the end of each phase. Blood pressure (BP) and heart rate measurements were with the patient ambulatory at 24 hours. All regimens required doubled doses at two weeks. Beta blocker, CCB, CEI, and ABL lowered BP (6 to 10 mm Hg) and BP load compared to PLA, while HCT and MOX did not. Converting enzyme inhibitor and HCT increased plasma renin activity (PRA), while BBL lowered PRA. The 24-hour urine analysis indicated a high dietary salt intake with a low potassium and calcium intake. The salivary electrolytes showed similar sodium and potassium concentrations, while chloride values were significantly higher in affected than nonaffected subjects. Thus, this monogenic form of hypertension resembles nonsalt-sensitive essential hypertension in that BBL, CCB, CEI, and ABL were effective, while HCT was not. The BP reduction was similar to other single drug trials in essential hypertension. The high salivary chloride values suggest an additional intermediary phenotype that may be related to electrolyte transport. These results raise the possibility that an as yet unknown hypertensive mechanism is operative in these subjects.

Adolescent↗
PubMed1997

Neurovascular compression at the ventrolateral medulla in autosomal dominant hypertension and brachydactyly.

BACKGROUND AND PURPOSE: Autosomal dominant hypertension with brachydactyly features severe hypertension that causes stroke usually before the age of 50 years. We recently characterized the hypertension as featuring normal renin, aldosterone, and catecholamine responses and mapped the gene responsible to chromosome 12p. Since angiography in an affected subject had earlier shown tortuous vessels, we performed magnetic resonance tomography (MRT) angiography to look for possible neurovascular anomalies (NVA), which have been previously associated with hypertension. NVA can be caused by a looping posterior inferior cerebellar or vertebral artery. Experimental and clinical evidence suggests that NVA may cause hypertension by a compression of the ventrolateral medulla. METHODS: We performed MRT in 15 hypertensive affected (aged 14 to 57 years) and 12 normotensive nonaffected (aged 12 to 59 years) family members. We then tested for linkage between the hypertension-brachydactyly phenotypes and the presence of NVA. RESULTS: All 15 affected persons had MRT evidence for NVA. All had left-sided posterior inferior cerebellar artery or vertebral artery loops, while 6 had bilateral NVA. None of the nonaffected family members had NVA. The phenotypes were linked with an LOD score of 9.2 given a penetrance of 99%. CONCLUSIONS: Autosomal dominant hypertension and brachydactyly regularly feature NVA, which is frequently bilateral. The early age at which NVA was identified suggests that the condition is primary. We suggest that NVA may be involved in the pathogenesis of this form of hypertension and perhaps essential hypertension as well. Further studies are necessary to address the question of causation.

Abnormalities, Multiple↗
PubMed1997

Twin zygosity. Automated determination with microsatellites.

OBJECTIVE: Twin zygosity determinations can be performed with anthropologic, serologic and genetic markers; however, these methods are more than occasionally inefficient, often expensive and sometimes inaccurate. We used microsatellites as DNA markers and developed a largely automated, rapid and efficient method of determining zygosity. STUDY DESIGN: We used five highly polymorphic short tandem repeat loci, coamplified by polymerase chain reaction (PCR) using fluorescence-labeled primers. Thirty-six samples were simultaneously analyzed by electrophoresis and laser detection. The PCR products were sized by automated fragment analysis. RESULTS: We typed 132 pairs of monozygotic (MZ) and dizygotic (DZ) twins. With five markers, the probability that any twin pair was MZ if all markers were concordant was 99%. CONCLUSION: This method is a rapid and reliable approach to zygosity detection.

Adult↗
PubMed1996

Oligonucleotide ligation assay (OLA) for the diagnosis of familial hypercholesterolemia.

More than half of all deaths in Western society are related to arteriosclerotic cardiovascular diseases. Inherited disturbances in the low-density-lipoprotein (LDL) receptor and similar lipid-related defects account for the majority of these deaths. Testing procedures thus far rely on total cholesterol, LDL cholesterol, high-density-lipoprotein cholesterol, and triglyceride determinations. These tests are not able to provide any genetic information. We have developed an oligonucleotide ligation assay (OLA) that enables us to screen for high-risk individuals by testing for 19 common mutations in the LDL receptor and the apolipoprotein B genes using an automated genotyping-based two-step protocol. The novel OLA uses oligomeric pentaethyleneoxide mobility modifiers. The automated test will be useful in screening large populations for genetic data to distinguish relative from absolute risk, as well as for cost-effective familial analysis.

Apolipoproteins B↗
PubMed1996

Severe autosomal dominant hypertension and brachydactyly in a unique Turkish kindred maps to human chromosome 12.

Finding genes that cause human hypertension is not straightforward, since the determinants of blood pressure in primary hypertension are multifactorial. One approach to identifying relevant genes is to elucidate rare forms of monogenic hypertension. A relevant mutation may provide a rational starting point from which to analyse the pathophysiology of a condition affecting 20% of the world's population. In 1973 a family with autosomal dominantly inherited brachydactyly and severe hypertension, where the two traits cosegregated completely, was described. We have now re-examined this kindred, and localized the hypertension and brachydactyly locus to chromosome 12p in a region defined by markers D12S364 and D12S87. As the renin-angiotensin-system and sympathetic nervous system respond normally in this form of hypertension, the condition resembles essential hypertension. This feature distinguishes this form of hypertension from glucocorticoid remediable aldosteronism and Liddle's syndrome, which are salt-sensitive forms of monogenic hypertension with very low plasma renin activity. We suggest that identification of the gene involved in hypertension and brachydactyly and its mutation will be of great relevance in elucidating new mechanisms leading to blood pressure elevation.

Adult↗
PubMed1996

Autosomal dominant hypertension and brachydactyly in a Turkish kindred resembles essential hypertension.

We examined a Turkish kindred with a unique form of autosomal dominant hypertension that cosegregates 100% with brachydactyly and maps to chromosome 12p. Affected adults were 10 to 15 cm shorter than unaffected people; however, their body mass index (27 kg/m2) was not different. Blood pressure increased steeply with age in the affected people so that by age 40 years, they had a mean blood pressure of 140 mm Hg, compared with 92 mm Hg in unaffected individuals. Complete clinical, roentgenographic, and laboratory evaluation was performed in 6 subjects, including 24-hour blood pressure measurements and humoral determinations before and after volume expansion with 2 L normal saline over 4 hours followed by volume contraction on the following day with a 20-mmol sodium diet and 40 mg furosemide at 8 AM, noon, and 4 PM. Two affected men aged 46 and 31 years; 3 affected women aged 40, 31, and 30 years; and 1 unaffected man aged 29 years were studied. Systolic pressures ranged from 170 to 250 mm Hg, and diastolic pressures ranged from 100 to 150 mm Hg in affected people; the unaffected man had a blood pressure of 120/70 mm Hg. Thyroid, adrenal, and renal functions were normal; electrolyte and acid-base statuses were normal. Calcium and phosphate homeostasis was normal. Day-night circadian blood pressure rhythm was preserved. The subjects were not salt sensitive; renin, aldosterone, and catecholamine values reacted appropriately to volume expansion and contraction. Affected people had mild cardiac hypertrophy and increased radial artery wall thickness. Fibroblasts from affected people grew more rapidly in culture than from unaffected people. We conclude that this novel form of inherited hypertension resembles essential hypertension.

Adult↗
PubMed1993

A phage T7 class-III promoter functions as a polymerase II promoter in mammalian cells.

A phage T7 class-III promoter (pT7), which is highly specific for T7 RNA polymerase in bacteria, was tested in mammalian cells for its specificity. After having shown that T7 RNA polymerase can transcribe from pT7 in the nucleus of stably transformed cells [Lieber et al., Nucleic Acids Res. 17 (1989) 8485-8493], we describe here that pT7 could also direct efficient intracellular gene expression in the absence of T7 RNA polymerase. Using the genomic human growth hormone-encoding gene and the firefly luciferase-encoding gene as reporters, we found expression levels comparable with those obtained with the Rous sarcoma viral promoter. Inhibition of expression with alpha-amanitin suggests that transcription is by RNA polymerase II. Binding studies with HeLa cell extracts clearly show that synthetic pT7 sequences are specifically bound (gel retardation) and that the promoter region is protected from DNase degradation. The experimental data, as well as the nucleotide sequence, suggest that pT7 has properties of an initiator element. Indeed, the activity of pT7 can be stimulated by the presence of an upstream element or an enhancer. These results have practical implications for the use of pT7 in mammalian expression vectors. Commercial pT7 plasmids can be used for both prokaryotic and eukaryotic expression systems.

Animals↗