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H Knoblauch

Publications and source records attributed to H Knoblauch.

At least 19 recordsLinked to original sources
PubMed2007

[Schizophrenia, human genetics and genetic counselling. Human genetic counselling as part of the psychiatric/psychotherapeutic treatment concept].

The human genome project has substantially increased our knowledge about the genetic basis of psychiatric diseases. In daily clinical practice the physician is asked about the diagnosis of genetically dependent diseases with an increased psychiatric risk, particularly schizophrenia group disorders, about the recurrence risk of psychiatric diseases in the relatives and children of the patients, on the use of psychopharmaceuticals during pregnancy and their potential consequences for the offspring, as well as psychopharmacogenetics. These questions will be dealt with in this contribution. At present, they receive too little attention, although genetic counselling might play an important role within the framework of psychiatric treatment, especially for schizophrenia. Such counselling should be seen as a component of the psychiatric/psychotherapeutic treatment concept and performed according to human genetic guidelines.

Genetic Counseling↗
PubMed2001

A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: implications for mutation analysis in pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is an inherited disorder of the elastic tissue with characteristic progressive calcification of elastic fibers in skin, eye, and the cardiovascular system. Recently mutations in the ABCC6 gene, encoding a transmembrane transporter protein, were identified as cause of the disease. Surprisingly, sequence and RFLP analysis for exon 9 with primers corresponding to flanking intronic sequence in diseased and haplotype negative members from all of our families and in a control population revealed either a homozygous or heterozygous state for the Q378X (1132C-->T) nonsense mutation in all individuals. With the publication of the genomic structure of the PXE locus we had identified the starting point of a large genomic segmental duplication within the locus in the cytogenetic interval defined by the Cy19 and Cy185 somatic cell hybrid breakpoints on chromosome 16p13.1. By means of somatic cell hybrid mapping we located this starting point telomeric to exon 10 of ABCC6. The duplication, however, does not include exon 10, but exons 1-9. These findings suggest that one or several copies of an ABCC6 pseudogene (psiABCC6) lie within this large segmental duplication. At least one copy contains exons 1-9 and maps to the chromosomal interval defined by the Cy163 and Cy11 breakpoints. Either this copy and/or an additional copy of psiABCC6 within Cy19-Cy183 carries the Q378X mutation that masks the correct identification of this nonsense mutation as being causative in pseudoxanthoma elasticum. Long-range PCR of exon 9 starting from sequence outside the genomic replication circumvents interference from the psiABCC6 DNA sequences and demonstrates that the Q378X mutation in the ABCC6 gene is associated with PXE in some families. These findings lead us to propose that gene conversion mechanisms from psiABCC6 to ABCC6 play a functional role in mutations causing PXE.

Alleles↗
PubMed2000

A pathway model of lipid metabolism to predict the effect of genetic variability on lipid levels.

Complex phenotypes such as serum lipid concentrations involve numerous genes and require the analysis of the combined effects of these gene products. We modeled the interactions of six key lipid metabolism genes by means of differential equations. We tested the model by inserting the effects of known mutations in the low-density lipoprotein receptor gene and the lipoprotein lipase gene, as well as the effects of a high-fat diet, and observed that the predictions corresponded very well to published measurements. Models such as the one that we present here will become indispensable for analyzing and understanding the effects of variation in multiple genes.

Carrier Proteins↗
PubMed2000

Support for linkage of familial combined hyperlipidemia to chromosome 1q21-q23 in Chinese and German families.

We examined familial combined hyperlipidemia (FCHL) families from nonisolated regions in Germany and China to see if we could corroborate support for a chromosome 1q FCHL locus in more general populations. We recruited 24 German families with 137 members, 92 of whom met the criteria of affected in terms of the low density lipoprotein (LDL) and triglyceride levels in excess of the 90th percentile for age and gender. In China, we recruited 12 families with a total of 81 members. All affected persons had total cholesterol concentrations >240 mg/dl and triglyceride concentrations >250 mg/dl. We examined the markers APOA2, D1S1677, D1S104, D1S194, D1S426, and D1S196. Two-point linkage analysis allowing for heterogeneity gave a maximum linkage of disorder score (HLOD) of 2.60 right over D1S194, estimating the proportion of linked families at 36%. This marker is adjacent to D1S104. The evidence for linkage was roughly the same both in the German (HLOD 1.40) and Chinese families (HLOD 1.52). Marker D1S194 is close to the retinoid X receptor (RXR) gene locus, which was found to be linked to triglyceride levels in an earlier twin study from our laboratory. We interpret our observations as encouraging support for the recent findings indicating the presence of a gene for FCHL on chromosome 1q. Furthermore, since DIS194 is adjacent to the gene for the RXR, we suggest that RXR is an attractive candidate for involvement in FCHL.

Adult↗
PubMed2000

Phenotypic variation and genetic heterogeneity in Léri-Weill syndrome.

Léri-Weill syndrome (LWS) or dyschondrosteosis represents a short stature syndrome characterised by the mesomelic shortening of the forearms and lower legs and by bilateral Madelung deformity of the wrists. Recently, mutations in the pseudoautosomal homeobox gene SHOX have been shown to be causative for this disorder. This gene has previously been described as the short stature gene implicated in Turner syndrome (TS). We studied 32 Léri-Weill patients from 18 different German and Dutch families and present clinical, radiological and molecular data. Phenotypic inter- and intrafamilial heterogeneity is a frequent finding in LWS, and phenotypic manifestations are generally more severe in females. In males, muscular hypertrophy is a frequent finding. To test for SHOX mutations we used FISH, Southern blot and SSCP analysis as well as long-range PCR and sequencing. We identified (sub)microscopic deletions encompassing the SHOX gene region in 10 out of 18 families investigated. Deletion sizes varied between 100 kb and 9 Mb and did not correlate with the severity of the phenotype. We did not detect SHOX mutations in almost half (41%) the LWS families studied, which suggests different genetic etiologies.

Adolescent↗
PubMed2000

Sudden death and Wegener's granulomatosis of the pituitary.

Involvement of brain parenchyma or meninges in ANCA-associated small-vessel vasculitis such as Wegener's granulomatosis (WG) is not uncommon. In contrast, involvement of the pituitary is exceedingly rare with only a few cases reported so far. The diagnosis is usually made on the basis of imaging techniques and abnormal pituitary function tests in the setting of active systemic vasculitis. However, histology-proven involvement of the pituitary by WG has not been reported so far. We report a case of WG with histology-proven granulomatous necrotizing inflammation of the pituitary and hypothalamo-pituitary stalk, disclosed at autopsy after the patient had died suddenly and unexpectedly in his sleep. In a setting of histology-proven WG, these findings were regarded as a pituitary manifestation of the disorder. A distinct cause of death could not be found, hence we speculate that hypothalamo-pituitary inflammation due to WG may have caused the sudden death in this patient.

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↗
PubMed2000

Technology and social interaction: the emergence of 'workplace studies'.

Despite the substantial body of literature concerned with the ways in which digital media are transforming contemporary society and institutional life, we have relatively little understanding of the ways in which new technologies feature in day to day organizational conduct and interaction. There is however a growing corpus of empirical research which places the situated and contingent character of new technologies at the heart of the analytic agenda, but as yet, these studies are relatively little known within sociology. They include ethnographies of command and control centres, financial institutions, the news media, and the construction industry. They address the ways in which tools and technologies, ranging from paper documents through to complex multimedia systems, feature in work and collaboration. In this paper, we discuss these so-called 'workplace studies' and consider their implications for our understanding of organizational conduct, social interaction and new technology.

Humans↗
PubMed1999

QT interval is linked to 2 long-QT syndrome loci in normal subjects.

BACKGROUND: The rate-corrected QT interval (QTc) is heritable, and the discovery of quantitative trait loci that influence the QTc would be an important step in identifying the genes responsible for life-threatening arrhythmias in the general population. We studied 66 pairs of unselected normal dizygotic (DZ) twin subjects and their parents in a sib-pair analysis. We tested for linkage of gene loci harboring genes known to cause the long-QT syndrome (LQT) to the quantitative trait QTc. METHODS AND RESULTS: We found genetic variance on QRS duration, QRS axis, T-wave axis, and QTc. Women had a longer QTc than men. Microsatellite markers were tested in the vicinity of the gene loci for the 5 known LQT genes. We found significant linkage of QTc with the loci for LQT1 on chromosome 11 and LQT4 on chromosome 4 but not to LQT2, LQT3, or LQT5. We also found linkage of the QRS axis with LQT2 and LQT3. CONCLUSIONS: We suggest that these quantitative trait loci may represent the presence of variations in LQT genes that could be important to the risk for rhythm disturbances in the general population.

Adult↗
PubMed1999

Linkage but lack of association for blood pressure and the alpha-adducin locus in normotensive twins.

BACKGROUND: alpha-adducin is a cytoskeletal protein involved with sodium-pump activity in the renal tubule. The alpha-adducin gene locus has been linked to hypertension and a polymorphism identified which is associated with hypertension; however, the role of the alpha-adducin gene locus in normal blood pressure regulation is not defined. We performed a combined linkage and association study in normotensive monozygotic (MZ) and dizygotic (DZ) twins and their parents to address this issue. METHODS: We studied 126 MZ and 70 DZ twin pairs and parents of DZ twins. Blood pressure values and responses to a cold pressor test were obtained. Cardiac dimensions were measured echocardiographically. Three microsatellites adjacent to the alpha-adducin gene were studied as well as the 460 Trp mutation in the alpha-adducin gene. RESULTS: We obtained strong evidence for linkage (P< 0.001) between the alpha-adducin gene locus and systolic blood pressure. However, we were not able to associate the 460 Trp mutation with higher blood pressures, cold pressor responses or cardiac dimensions. CONCLUSIONS: The alpha-adducin gene locus is relevant to blood pressure regulation in normal subjects. Failure to find an association between higher blood pressures and the 460 Trp mutation suggests that this mutation may become important only when hypertension is triggered, or that other variations in alpha-adducin are present which have not yet been discovered.

Adolescent↗
PubMed1999

Peroxisome proliferator-activated receptor gamma gene locus is related to body mass index and lipid values in healthy nonobese subjects.

The peroxisome proliferator-activated receptor gamma (PPARgamma) gene has been implicated in morbid obesity and is important to lipid and carbohydrate metabolism. However, the relevance of gene variations in healthy nonobese subjects has not been defined. We recruited monozygotic and dizygotic healthy nonobese twin subjects to test the hypothesis that the PPARgamma gene is important to body mass index and lipid concentrations in healthy nonobese subjects. Both linkage and association strategies were used in the same dizygotic twins. The PPARgamma gene locus was linked (P<0.01) to high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and body mass index as quantitative traits. A biallelic variant in the PPARgamma gene was associated with high-density lipoprotein cholesterol and body mass index (P<0.05). We also looked for linkage between the same variables and the retinoic X receptor gene locus. This locus was linked to total and low-density lipoprotein cholesterol as well as triglycerides. We conclude that the PPARgamma gene is highly relevant to lipid metabolism and body mass index, not only in the morbidly obese but also in healthy nonobese subjects. The same appears to be true for its binding partner. Sequencing these genes in twins would serve to identify gene variations contributing to body mass index and lipid concentrations in healthy nonobese subjects.

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↗
PubMed1999

Fetal trisomy 10 mosaicism: ultrasound, cytogenetic and morphologic findings in early pregnancy.

We report the ultrasound, cytogenetic and morphologic findings in a case of trisomy 10 mosaicism prenatally detected by chorionic villus sampling (CVS). CVS sampling was carried out at the 13th week of gestation because of ultrasound diagnosis of hydrops fetalis and hygroma colli. Trisomy 10 mosaicism was diagnosed in cells from the cytotrophoblast (short-term culture) and the chorionic villus core (long-term culture). Fetal mosaicism was confirmed after termination of pregnancy in umbilical cord cells, placenta and fetal skin fibroblasts.

Adult↗