Biomedical subjects

Thomas Sander

Publications and source records attributed to Thomas Sander.

40 records · Page 3Linked to original sources

PubMedDate not supplied

A new EF-hand containing gene EFHC2 on Xp11.4: tentative evidence for association with juvenile myoclonic epilepsy.

Genetic factors play a major role in the etiology of idiopathic generalized epilepsies (IGE). An oligogenic or polygenic predisposition is suspected in the majority of families with common IGE syndromes. It has been hypothesized that some IGE genes might increase the general level of neuronal excitability while others specify the age of onset and the seizure type. The EFHC1 gene on 6p12-p11 was previously described as the first susceptibility gene for juvenile myoclonic epilepsy (JME). EFHC1 codes for a protein of unknown function that is characterized by Ca2+-binding EF-hand motifs and DM10 domains. We have now cloned the brain-expressed paralog EFHC2 (Xp11.3) and carried out an association study of six single nucleotide polymorphisms (SNPs) in a large sample of 654 German IGE patients and 662 population controls. A tentative association was found between the amino acid exchange S430Y in exon 9 of EFHC2 and 97 male JME patients (chi2=4.705, d.f.=1, P=0.030; OR=2.17; 95-CI: 1.06-4.43). The allelic association was even stronger for the 81 males with "classical" JME (JME without absence seizures) (chi2=6.06, d.f.=1, P=0.014; OR=2.46; 95-CI: 1.18-5.13). An association with the gonosomal gene EFHC2 would be in accordance with the observed preponderance of maternal inheritance in JME maternal inheritance of JME. Independent replication studies are needed to further analyse the tentative association described here.

Chi-Square Distribution↗

PubMedDate not supplied

No association between common variations in the human alpha 2 subunit gene (ATP1A2) of the sodium-potassium-transporting ATPase and idiopathic generalized epilepsy.

Quantitative trait loci studies in inbred mice have identified a locus on chromosome 1 (Szs1) of fundamental importance to seizure susceptibility. High-ranking candidate genes in this susceptibility region include KCNJ9, KCNJ10 and ATP1A2. We performed a systematic mutation scan of the coding region of the human ATP1A2 gene and performed a case-control association study with seven common markers. Genotypes were assessed in 152 idiopathic generalized epilepsy (IGE) patients of German ancestry and 111 healthy German controls for all seven polymorphisms. No significant differences were found in genotype or allele frequencies for any of the variations between the IGE patients and controls. No haplotypes were associated with IGE when compared to controls. Linkage disequilibrium was demonstrated throughout the gene. Results suggest that the polymorphisms we studied in the ATP1A2 gene do not represent major susceptibility factors for common forms of IGE.

DNA↗

PubMedDate not supplied

Toxicity-indicating structural patterns.

We describe a toxicity alerting system for uncharacterized compounds, which is based upon comprehensive tables of substructure fragments that are indicative of toxicity risk. These tables were derived computationally by analyzing the RTECS database and the World Drug Index. We provide, free of charge, a Java applet for structure drawing and toxicity risk assessment. In an independent investigation, we compared the toxicity classification performance of naive Bayesian clustering, k next neighbor classification, and support vector machines. To visualize the chemical space of both toxic and druglike molecules, we trained a large self-organizing map (SOM) with all compounds from the RTECS database and the IDDB. In summary, we found that a support vector machine performed best at classifying compounds of defined toxicity into appropriate toxicity classes. Also, SOMs performed excellently in separating toxic from nontoxic substances. Although these two methods are limited to compounds that are structurally similar to known toxic substances, our fragment-based approach extends predictions to compounds that are structurally dissimilar to compounds used in the training set.

Bayes Theorem↗

PubMedDate not supplied

Migrainous vertigo: mutation analysis of the candidate genes CACNA1A, ATP1A2, SCN1A, and CACNB4.

BACKGROUND: Migrainous vertigo (MV) is increasingly recognized as a common cause of episodic vertigo. MV displays several clinical similarities with familial hemiplegic migraine (FHM) and episodic ataxia type 2 (EA-2), which have been linked to mutations in 3 genes, CACNA1A, encoding a neuronal calcium channel alpha subunit, ATP1A2, encoding a catalytic subunit of a Na(+)/K(+)-ATPase, and most recently the voltage-gated sodium channel SCN1A. The present study explored the hypothesis that mutations in CACNA1A, ATP1A2, SCN1A, and the calcium channel beta(4) subunit CACNB4 confer susceptibility to MV. METHODS: Mutation analysis of the coding exons and exon/intron junctions of CACNA1A, ATP1A2, SCN1A, and CACNB4 was performed in 14 unrelated MV patients by conformation sensitive gel electrophoresis and automated sequence analysis. RESULTS: Analysis of the 4 candidate genes in the 14 MV patients resulted in the identification of a total of 26 sequence variants. The silent substitution D29D in CACNB4 was observed in 2 MV patients and was not present in 46 ethnically matched control DNA samples. The remaining variants were also observed in control DNA samples and the allele frequencies of variants that resulted in amino acid substitutions were not significantly different between patients and controls. CONCLUSIONS: Based on this group of patients there is no evidence that the genes causing FHM and EA-2 represent major susceptibility loci for MV.

Adolescent↗