184 research outputs found
Integrated genetic-map of human-chromosome-2
No full textA framework genetic map of human chromosome 2 is described, integrating data from the Centre d'Étude du Polymorphisme Humain (CEPH) version 6 database, the CEPH chromosome 2 consortium database, the National Institute of Health (NIH)/CEPH Collaborative Mapping group and other laboratories. A comprehensive map is also presented, showing regional locations of a large number of additional loci. The framework map is used to identify an informative set of meiotic breakpoints within the CEPH families, and the utility of this information for mapping new markers is discussed. The degree of typing error within the data set is estimated, as are the sex-specific interference parameters. A location database for these genetic and additional cytogenetic data is constructed using algorithms which map genetic distances on to a physical scale, and the potential for this approach to aid the integration of genetic and physical data is examined
Evaluation of fine mapping strategies for a multifactorial disease locus: systematic linkage and association analysis of IDDM1 in the HLA region on chromosome 6p21
No full textThe positional cloning of multifactorial disease genes is a major challenge in human genetics. We have therefore empirically tested the utility of the available polymorphic microsatellite map to locate the already identified type 1 diabetes locus IDDM1 (sibling risk/population prevalence ratio lambda(s)= 2.7) within a 14 Mb region of chromosome 6p21 linked to disease. In a two-stage approach to fine mapping, linkage was evaluated in 385 affected sib-pair families using 13 evenly spaced polymorphic microsatellite markers. The whole 14 Mb showed strong linkage. Then, each marker was analysed for evidence of allelic association, revealing evidence of disease association at one marker located within the 95% confidence interval of 1.7 cM obtained by linkage. Analysis of an additional 12 markers flanking this marker revealed a highly specific region of 570 kb associated with disease ( P = 7.5 x 10(-35)), which included the HLA class II genes, known to be the primary determinants of IDDM1. The peak of association was as close as 85 kb centromeric of the disease-predisposing class II gene HLA-DQB1. We investigated the importance of the underlying inter-marker linkage disequilibrium, marker informativity and recombination for fine mapping and demonstrate that the majority of disease association in the region can be explained by linkage disequilibrium with the class II susceptibility genes. Recombination within the major histocompatibility complex was rare and nearly absent in the class III region. We demonstrate that fine mapping of a multifactorial disease gene is possible with high accuracy even in a region with extraordinary linkage disequilibrium across distances of several Mb. The results will be applicable to association studies of disease loci with lambda(s)values <2.7 except that much larger data sets will be required
Conditional ETDT analysis of the Human Leukocyte Antigen region in type 1 diabetes
No full textSeveral studies have indicated that additional genes in the major histocompatibility complex (MHC) region, other than the class II genes HLA-DQB1 and -DRB1 (the IDDM1 locus), may contribute to susceptibility and resistance to type 1 diabetes. The relative magnitude of these non- DR/DQ effects is uncertain and their map location is unknown owing to the extraordinary linkage disequilibrium that extends over the 3.5 Mb of the MHC. The homozygous parent test has been proposed as a method for detection of additional risk factors conditional on HLA-DQB1 and -DRB1. However, this method is inefficient since it uses only parents homozygous for the primary disease locus, the DQB1-DRB1 haplotype. To overcome this limitation, Conditional ETDT was used in the present report to test for association conditional on the DQB1-DRB1 haplotype, thereby allowing all parents to be included in the analysis. First, we confirm in UK and Sardinian type 1 diabetic families that allelic variation at HLA-DRB1 has a very significant effect on the association of DQB1 and vice versa. The Conditional ETDT was then applied to the HLA TNF (tumour necrosis factor) region and microsatellite marker D6S273 region, both of which have been reported to contribute to IDDM1 independent of the HLA-DQB1-DRB1 genes. We found no evidence for a major role for either of these two regions in IDDM1
Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease
No full textAlleles of HLA class II genes DQB1, DQA1, and DRB1 in the MHC region are major determinants of genetic predisposition to type 1 diabetes (T1D). Several alleles of each of these three loci are associated with susceptibility or protection from disease. In addition, relative risks for some DR-DQ genotypes are not simply the sum or product of the single haplotype relative risks. For example, the risk of the DRB1*03-DQB1*02/DRB1*0401-DQB1*0302 genotype is often found to be higher than for the individual DRB1*03-DQB1*02andDRB1*0401-DQB1*0302 homozygous genotypes. It has been hypothesized that this synergy or epistasis occurs through formation of highly susceptible trans-encoded HLA-DQ(alpha1, beta1) heterodimers. Here, we evaluated this hypothesis by estimating the disease associations of the range of DR-DQ genotypes and their inferred dimers in a large collection of nuclear families. We determined whether the risk of haplotypes in DRB1*0401-DQB1*0302-positive genotypes relative to the DRB1*03-DQB1*02-positive genotypes is different from that of DRB1*01-DQB1*0501, which we used as a baseline reference. Several haplotypes showed a different risk compared to DRB1*01-DQB1*0501, which correlated with their ability to form certain trans-encoded DQ dimers. This result provides new evidence for the potential importance of trans-encoded HLA DQ molecules in the determination of HLA-associated risk in T1D
FREQUENCY AND INHERITANCE OF MICRODELETIONS 15Q13.3, 15Q11.2 AND 16P13.1 IN IGE-PATIENTS WITH PHOTOPAROXYSMAL RESPONSE
No full textAn electrophysiological characterizaton of Kv7.2 and Nav1.1 channel mutations in genetic epilepsy
No full textMost genetically determined epilepsies are caused by gene mutations in genes that encode for ion channels and receptors. Functional analysis of these protein mutants shows changes in voltage dependency and/or kinetics or a complete loss of channel function via different mechanisms. Nevertheless, the severity of the epileptic seizures is not only determined by a specific gene mutation, but genetic background, modifying genes and genetic compensatory factors are playing a crucial role in the phenotypic outcome of patients
Determinants of variable disease severity in SCN1A-related phenotypes and X-chromosomal epilepsy syndromes
No full textDravet syndrome Dravet syndrome is one of the most well-known genetic epilepsy syndromes. The main characteristics of the disease are early onset intractable epileptic seizures in the first year of life, accompanied by a delayed psychomotor development in the second year of life, resulting in mild to severe intellectual disability in most patients. Mutations in one of both copies of the SCN1A-gene are the cause of disease in the majority of Dravet syndrome patients. Phenotypic variability Pathogenic variants in SCN1A can give rise to not only Dravet syndrome, but also to milder phenotypes, such as genetic epilepsy with febrile seizures plus (GEFS+), febrile seizures plus (FS+) and febrile seizures. This discrepancy can be partly explained by the different mutation types that are associated with the respective disorders. This however does not explain all differences between patients with SCN1A-related epilepsy: patients with similar mutations may show a wide phenotypic variability and even the exact same SCN1A mutation does not always result in the same phenotype. For parents of young patients, it is understandably very important to accurately predict the clinical course after a pathogenic SCN1A variant has been detected. In this thesis, we have investigated several potential modifiers that may influence clinical outcomes of genetic epilepsy syndromes, to ultimately improve counseling of patients and/or parents. Influence of modifiers We conclude that many different modifiers influence the severity of SCN1A-related disease. Examples are modifier genes, variants in regulatory regions of the SCN1A-gene, medication use and mosaicism. Mosaicism does not only influence the severity of SCN1A-related phenotypes, but also that of two X-linked epilepsy syndromes we have researched (PCDH19- and KIAA2022-related epilepsy). We can investigate several of these modifiers in individual patients already. When detection of mosaicism is implemented in regular diagnostics, parents can be better informed regarding the expected severity of the disease and the recurrence risk for future children. We also show that the age at which a first afebrile seizure occurs is a good predictor for disease severity. We furthermore show that the prolonged use of contra-indicated medication has a negative effect on mental development. We therefore conclude that it is of great importance to detect SCN1A pathogenic variants at a young age, before maintenance treatment is initiated and contra-indicated medication can be avoided
Removal of total ammoniacal nitrogen from reject water through selective electrodialysis reversal and bipolar electrodialysis
No full textThe removal of ammonium and ammonia, represented as total ammoniacal nitrogen (TAN), from reject water through electro-dialysis (ED) and bipolar membrane electrodialysis (BPMED) encounters challenges such as organic fouling, NH3 back-diffusion, and high energy consumption. The efficacy of electrodialysis reversal (EDR) combined with bipolar membrane electrodialysis using cation-exchange membranes (BPC) was assessed as a more practical configuration (EDR + BPC). Additionally, a novel configuration involving monovalent selective cation-exchange membranes (MSCEMs) in an EDR + BPC setup (SEDR + BPC) was investigated. Comparisons were made among BPMED, EDR + BPC, and SEDR + BPC under three load ratios (LN) of 0.8, 1, and 1.3 during continuous operation. The innovative SEDR + BPC configuration, with an LN of 0.8, exhibited the lowest energy consumption for transported TAN (ETAN) at 4.4 MJ·kgN−1 removal and achieved the highest TAN removal efficiency of 78 % with an LN of 1.3. In contrast to conventional BPMED, SEDR + BPC allowed for the recovery of potentially back-diffused NH3 into the acid chamber, minimizing transport losses. Furthermore, scaling in the base chamber was reduced due to the contribution of MSCEMs when applying an LN of 0.8. The MSCEMs increased the molar ratio of TAN over (Mg2+ + Ca2+) in the concentrate and decreased it in the diluate. EDR + BPC and SEDR + BPC configurations exhibited stable and lower cell resistance throughout the operation compared to BPMED, attributed to their ability to generate higher concentration gradients. The results clearly demonstrated the feasibility of low-energy TAN removal from real reject water from sludge anaerobic digestion using the SEDR + BPC setup.Sanitary Engineerin
The HLA-DPB1-associated component of the IDDM1 and its relationship to the major loci HLA-DQB1,-DQA1, and-DRB1
No full textThe major histocompatibility complex (MHC) HLA region on chromosome 6p21 contains the major locus of type 1 diabetes (IDDM1). Common allelic variants at the class II HLA-DRB1, -DQA1, and -DQB1 loci account for the major part of IDDM1. Previous studies suggested that other MHC loci are likely to contribute to IDDM1, but determination of their relative contributions and identities is difficult because of strong Linkage disequilibrium between MHC loci. One prime candidate is the polymorphic HLA-DPB1 locus, which (with the DPA1 locus) encodes the third class II antigen-presenting molecule. However, the results obtained in previous studies appear to be contradictory. Therefore, we have analyzed 408 white European families (200 from Sardinia and 208 hom the U.K.) using a combination of association tests designed to directly compare the effect of DPB1 variation on the relative predisposition of DR-DQ haplotypes, taking into account linkage disequilibrium between DPB1 and the DRB1, DQA1, and DQB1 loci. In these populations, the overall contribution of DPB1 to IDDM1 is small. The main component of the DPB1 contribution to IDDM1 in these populations appears to be the protection associated with DPB1*0402 on DR4-negative haplotypes. me suggest that the HLA-DP molecule itself contributes to IDDM1
An Ultrasonically-Powered System for 1.06mm<sup>3</sup> Implantable Optogenetics and Drug Delivery Dust
No full textThis brief presents an ultrasonically powered micro-system for deep tissue optogenetic stimulation. The developed system is composed of a Base for Powering and Controlling (BPC) and an implantable Dust for optogenetics and drug delivery. The Dust consists of a piezoelectric crystal, a rectifier chip, and a micro-scale custom-designed light-emitting-diode (μ LED) integrated, miniaturized, and envisioned to be used for freely moving animal studies. The proposed Dust operates in frequencies up to 5 MHz, power levels in the 0-10 mW range, achieves start-up within 1.8~μ s at 2.9 MHz operating frequency at 14.4 mW/mm2 ultrasound power density, and 98.1% chip efficiency at 2 mW input power. With the BPC implemented and attached to ( 500~μ m )3 PZT4 crystals, set to 60 V at 2.8 MHz operating frequency at 3 mm distance in demineralized water, the dust delivered up to 6 mW to its load (μ LED for optogenetics), which translates to 0.11% total system efficiency.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Bio-Electronic
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