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Thomas Sander

Publications and source records attributed to Thomas Sander.

At least 37 records · Page 2Linked to original sources
PubMed2005

Association analysis of malic enzyme 2 gene polymorphisms with idiopathic generalized epilepsy.

PURPOSE: Linkage disequilibrium mapping revealed allelic and haplotypic associations between single-nucleotide polymorphisms (SNPs) of the gene encoding the malic enzyme 2 (ME2) and adolescent-onset idiopathic generalized epilepsy (IGE). Homozygote carriers of the associated ME2 haplotype had a sixfold higher risk of IGE compared with any other genotype. The present population-based association study tested whether genetic variation of the ME2 gene confers susceptibility to common IGE syndromes in the German population. METHODS: The study included 666 German healthy control subjects and 660 German IGE patients (IGE group), of which 416 patients had an age at onset in adolescence (IGEado group). Genotyping was performed for six SNPs and one dinucleotide repeat polymorphism, all located in the ME2 region. RESULTS: Neither allele nor genotype frequencies of any ME2 polymorphism differed significantly between the controls and the IGE groups (p > 0.22). No hint of an association of the putative risk-conferring haplotype was seen, when present homozygously, in both IGE groups compared with controls (p > 0.18). CONCLUSIONS: These results do not support previous evidence that genetic variation of the ME2 gene predisposes to common IGE syndromes. Thus if a recessively inherited ME2 mutation is present, then the size of the epileptogenic effect might be too small or not frequent enough to detect it in the present IGE sample.

Age of Onset↗
PubMed2004

Polymorphisms in the NMDA subunit 2B are not associated with alcohol dependence and alcohol withdrawal-induced seizures and delirium tremens.

OBJECTIVE: Ethanol-inhibited glutamatergic neurotransmission has been shown to mediate pathophysiological mechanisms in the development of alcoholism, including withdrawal symptoms. NMDA-receptor 2B (NR2B) is a subunit that confers a high sensitivity to ethanol-induced inhibition. Previously we had reported a lack of association between the single nucleotide polymorphism (SNP) rs1806201 in the NR2B gene (GRIN2B) and alcoholism. Shortly thereafter, an association between the polymorphism and early-onset alcoholism has been reported. One aim of the present study was to test whether the association between the GRIN2B polymorphism rs1806201 and early-onset alcoholism can be replicated in a larger sample. Moreover, we hypothesized that another genetic variation within GRIN2B (rs1806191) may have an effect in the etiology of alcoholism or withdrawal-related traits. METHODS: We extended our original study sample to a size of 377 patients and 464 healthy volunteers and performed a replication study, including the second GRIN2B SNP. Associations between allele, genotype and haplotype frequencies of the two polymorphisms and alcoholism as well as with patients' phenotypes were investigated. RESULTS: No associations were found between any of the two polymorphisms, tested individually or as haplotypes, and alcoholism, respectively withdrawal-related traits. CONCLUSION: Neither the analyzed SNPs nor any of their haplotypes likely modify susceptibility to alcohol dependence or withdrawal-related phenotypes.

Adult↗
PubMed2003

Candidate gene analysis of the human metabotropic glutamate receptor type 4 (GRM4) in patients with juvenile myoclonic epilepsy.

Hereditary factors play a major role in the genetically complex etiology of juvenile myoclonic epilepsy (JME). Linkage studies in families of JME probands suggest a susceptibility locus (EJM1) for idiopathic generalized epilepsy (IGE) in the chromosomal region 6p21.3 near the HLA region. The gene encoding the metabotropic glutamate receptor type 4 (GRM4) has been localized within the EJM1-region and represents a high-ranking candidate gene. Therefore, we have sequenced the coding regions and regulatory GRM4 sequences in 20 IGE probands who were derived from families of JME probands providing positive linkage evidence to the HLA-DQ locus. Our mutation analysis detected three synonymous exonic single nucleotide polymorphisms (SNP; exon-7: c.1455T > C, exon-8: c.2002A > G, exon-10: c.2733C > T), one SNP in the 3'-untranslated region (c.2890A > G), and two intronic SNPs (intron-3: IVS3 + 2732A > G, intron-7: IVS7 + 39C > T). None of the identified SNPs was likely to affect receptor function or gene expression. The population-based association study did not show significant differences in the allele and genotype frequencies of the common c.1455T > C SNP between 144 German JME probands and 144 healthy population controls (P > 0.84). Likewise, the family-based transmission disequilibrium test did not indicate a preferential transmission of exon-7 SNP alleles in 31 informative parent-child transmissions (P = 0.86). Our results provide no evidence that genetic variation of the GRM4 gene confers susceptibility to JME-related IGE syndromes.

Adolescent↗
PubMed2003

Genotypic association of exonic LGI4 polymorphisms and childhood absence epilepsy.

The LGI4 gene is located in a region linked to benign familial infantile convulsions (BFIC) and idiopathic generalized epilepsy. Screening of the LGI4 coding region in BFIC and childhood absence epilepsy (CAE) revealed several frequent exonic polymorphisms. A genotypic association was found for the c.1914GC --> AT polymorphism in 42 CAE patients compared with 110 population controls (chi2 = 6.66, df = 1, P = 0.01), providing evidence for a so far undetected susceptibility allele for CAE in the LGI4 region.

DNA Mutational Analysis↗
PubMed2003

Association of the G1947A COMT (Val(108/158)Met) gene polymorphism with prefrontal P300 during information processing.

BACKGROUND: A common functional polymorphism, G1947A, of the catechol-O-methyltransferase (COMT) enzyme has gained interest in schizophrenia research because of its critical involvement in cortical dopamine catabolism and frontal lobe function. An assumed mechanism of dopamine is the reduction of noise in prefrontal neural networks during information processing. Therefore, the hypothesis was tested whether a variation of the COMT genotype is associated with prefrontal noise, which is in part reflected by the frontal P300 amplitude. It was predicted that homozygous Met allele carriers have a lower frontal P300 amplitude. METHODS: The P300 component (auditory oddball) was recorded in 49 schizophrenic patients and 170 healthy control subjects. Three single nucleotide polymorphisms (SNPs) of the COMT gene (G1947A, C1883G, and G1243A) were investigated. RESULTS: We observed a significant effect of G1947A COMT genotype on frontal P300 amplitude, with evidence for a genotype x diagnosis interaction. Lower frontal P300 amplitudes occurred in homozygous carriers of the Met allele, particularly in schizophrenic patients. CONCLUSIONS: The association of the frontal P300 amplitude with the G1947A COMT genotype further emphasizes the functional role of this SNP. As the finding was mainly observed in schizophrenic patients, this may indicate that additional factors are required to interact with COMT genotype to affect prefrontal function. The smaller frontal P300 amplitude in Met carriers suggests that the amount of noise in prefrontal neural networks during information processing might be in part under genetic control, which is mediated by dopamine.

Acoustic Stimulation↗
PubMed2003

Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.

Idiopathic generalized epilepsy (IGE) is an inherited neurological disorder affecting about 0.4% of the world's population. Mutations in ten genes causing distinct forms of idiopathic epilepsy have been identified so far, but the genetic basis of many IGE subtypes is still unknown. Here we report a gene associated with the four most common IGE subtypes: childhood and juvenile absence epilepsy (CAE and JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal seizures on awakening (EGMA; ref. 8). We identified three different heterozygous mutations in the chloride-channel gene CLCN2 in three unrelated families with IGE. These mutations result in (i) a premature stop codon (M200fsX231), (ii) an atypical splicing (del74-117) and (iii) a single amino-acid substitution (G715E). All mutations produce functional alterations that provide distinct explanations for their pathogenic phenotypes. M200fsX231 and del74-117 cause a loss of function of ClC-2 channels and are expected to lower the transmembrane chloride gradient essential for GABAergic inhibition. G715E alters voltage-dependent gating, which may cause membrane depolarization and hyperexcitability.

Adolescent↗
PubMed2003

Association of EEG coherence and an exonic GABA(B)R1 gene polymorphism.

The GABA(B) receptor 1 gene is mapped to chromosome 6p21.3 within the HLA class I region close to the HLA-F gene. Susceptibility loci for epilepsy and schizophrenia have been mapped in this region. Based on pharmacological evidence, it has been suggested that GABA(B) receptors may play a crucial role in the synchronization of EEG oscillations, which in turn can be abnormal in neuropsychiatric disorders. In the present study, the hypothesis was tested, whether three exonic variants of the gene encoding the human GABA(B) receptor (GABA(B)R1) modify cortical synchronization measured as scalp-recorded EEG-coherence. Two principal components of EEG coherence (frontal coherence, parietotemporal coherence) were investigated in 104 healthy subjects during three conditions: resting EEG, activated EEG, and event-related EEG. No significant associations were found between the frontal coherence component and any polymorphism or between the parietotemporal coherence component and the exon 1a1 polymorphism. However, parietotemporal coherence showed statistically highly significant associations across all three experimental conditions with exon 7 and trend associations with exon 11. The results provide evidence that the translated polymorphism of exon 7 may be functionally meaningful and impact cortical EEG oscillations. Since variations of EEG coherence have been described for several neuropsychiatric disorders, the present association should be tested in clinical samples using EEG coherence as an intermediate phenotype.

Adult↗
PubMed2003

Association analysis of exonic variants of the GABA(B)-receptor gene and alpha electroencephalogram voltage in normal subjects and alcohol-dependent patients.

Based on pharmacologic evidence, it has been suggested that GABA(B) receptors may play a crucial role in the generation of alpha-electroencephalogram (EEG) oscillations. We tested whether three exonic variants of the gene encoding the human GABA(B) receptor (GABA(B)R1) modify scalp-recorded alpha-EEG voltage. One hundred twenty-eight patients suffering from alcoholism and 114 normal subjects were investigated. Alcohol-dependent patients were included because evidence exists that the frequently observed alpha low voltage in these subjects is at least partly a trait variable. Logistic regression analyses revealed no associations between alpha-EEG voltage and polymorphic variations in exon 1a1 or exon 11. A significant interaction was observed for an exon 7 substitution polymorphism and diagnosis (P = 0.009). Post hoc analyses showed an association between EEG phenotype and exon 7 genotype in normal subjects only. It is concluded that this particular association may only be observable under physiologic conditions and that alpha low voltage in alcohol-dependent subjects is under the control of either different genes or that it is related to the disease process.

Adult↗
PubMed2003

Exploration of a putative susceptibility locus for idiopathic generalized epilepsy on chromosome 8p12.

PURPOSE: A recent genome-wide scan revealed a major susceptibility locus for idiopathic generalized epilepsies (IGEs) in the chromosomal region 8p12 in 32 IGE families without members with juvenile myoclonic epilepsy (JME). This study explored the presence of an IGE locus in the chromosomal region 8p12. METHODS: Our study included 176 multiplex families of probands with common IGE syndromes. Parametric and nonparametric multipoint linkage analyses were carried out between the IGE trait and six microsatellite polymorphisms encompassing the putative susceptibility locus. To explore the associated phenotype-genotype relation, two distinct subgroups of families were selected by the presence (n = 64) or absence (n = 112) of a family member with JME. To adjust the phenotypic spectrum toward adolescent-onset IGEs, a third subgroup of 28 families without JME was chosen through an IGE proband with seizure onset at age 10-20 years. RESULTS: Parametric and nonparametric multipoint linkage analyses provided no evidence for linkage between IGE and markers encompassing the putative IGE locus in the chromosomal region 8p12. Furthermore, we found no hint of linkage along the candidate region in any of the three family subgroups. CONCLUSIONS: We failed to provide evidence for a major IGE locus in the chromosomal region 8p12. On the contrary, these parametric linkage results provide strong evidence against linkage across the candidate region under a broad range of genetic models. If there is a susceptibility locus for IGE in the chromosomal region 8p12, then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.

Adult↗
PubMed2002

No evidence for a susceptibility locus for idiopathic generalized epilepsy on chromosome 18q21.1.

A recent genome-wide scan showed strong evidence for a major locus for common syndromes of idiopathic generalized epilepsy (IGE) at the marker D18S474 on chromosome 18q21.1 (LOD score 4.5/5.2 multipoint/two-point). The present replication study tested the presence of an IGE locus in the chromosomal region 18q21.1. Our linkage study included 130 multiplex families of probands with common IGE syndromes. Eleven microsatellite polymorphisms encompassing a candidate region of 30 cM on either side of the marker D18S474 were genotyped. The two-point homogeneity LOD score for D18S474 showed strong evidence against linkage at the original linkage peak (Z = -18.86 at theta(m = f) = 0.05), assuming a recessive mode of inheritance with 50% penetrance. Multipoint parametric heterogeneity LOD scores < -2 were obtained along the candidate region when proportions of linked families greater than 35% were assumed under recessive inheritance. Furthermore, non-parametric multipoint linkage analyses showed no hint of linkage throughout the candidate region (P > 0.19). Accordingly, we failed to support evidence for a major IGE locus in the chromosomal region 18p11-18q23. If there is a susceptibility locus for IGE in this region then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.

Adolescent↗
PubMed2002

Allelic variants of the functional promoter polymorphism of the human serotonin transporter gene is associated with auditory cortical stimulus processing.

The loudness dependence (LD) of the auditory-evoked N1/P2 component has been shown to be related to the central serotonergic neurotransmission. Allelic variants in the promoter region of the 5-hydroxytryptamine transporter (5-HTT) gene were shown to modulate serotonergic activity. It was hypothesized that the three genotypes (l/l, s/l, s/s) differ with respect to LD. Allelic variants of the 5-HTT promoter region and LD at the Cz electrode were determined in 185 healthy subjects prospectively. A significant association was found between LD and genotype (ANOVA: F=4.172, p=0.017). Individuals homozygous for the l allele exhibited a weaker LD compared to heterozygous subjects. The results are consistent with the reported association between 5-HTT genotype and serotonin transport capacity in lymphoblasts, and indicate that auditory stimulus processing is associated with genetic variants of the brain serotonergic system. The LD may serve as endophenotype in human serotonin research.

Adult↗
PubMed2002

Sequencing of the GRIK1 gene in patients with juvenile absence epilepsy does not reveal mutations affecting receptor structure.

Hereditary factors play a major role in the etiology of juvenile absence epilepsy (JAE) that is a common subtype of idiopathic generalized epilepsy (IGE). Sander et al. [1997: Am J Med Genet 74:416-421] reported an allelic association of JAE with the nine-copy allele of a tetranucleotide repeat polymorphism in the third intron of the kainate-selective GluR5 receptor gene (GRIK1) and supportive evidence for linkage of IGE to GRIK1 in families of JAE probands. These findings suggest that a major genetic determinant of GRIK1 confers susceptibility to JAE. Assuming that the GRIK1 tetranucleotide repeat polymorphism is unlikely to have functional relevance itself, we have sequenced the coding regions and regulatory sequences of the GRIK1 gene in eight JAE patients who carry the nine-repeat allele of the GRIK1 tetranucleotide repeat polymorphism to detect a putative functional GRIK1 mutation that is in linkage disequilibrium with the nine-repeat allele. Seven of them were derived from families showing positive evidence for linkage to GRIK1. Our mutation analysis of coding regions and splice junctions revealed only two silent polymorphisms (A522C and C1173T) out of the five SNPs present in public databases and no mutations affecting protein structure. No significant differences were found in the allele frequencies of the detected polymorphisms between the JAE patients and controls. High levels of sequence conservation were also found in the promoter, in the 5' and both the 3' untranslated regions and in the RNA secondary structure involved in the editing reaction. The results presented indicate that mutations in the coding sequences, in the intron-exon boundaries and in the main regulatory regions of the GRIK1 are not commonly involved in the etiology of JAE.

Adolescent↗
PubMed2002

Tandem pore domain K(+)-channel TASK-3 (KCNK9) and idiopathic absence epilepsies.

Recently, the gene coding for the tandem pore domain K(+)-channel TASK-3 (KCNK9) has been localized to the chromosomal region 8q24. Because mutations in ion channel genes have been recognized as an important factor in the etiology of abnormal neuronal excitability, TASK-3 is an interesting candidate gene for epilepsies linked to 8q24. We therefore performed a mutation analysis of the TASK-3 gene in 65 patients with childhood and juvenile absence epilepsy. Only one silent nucleotide exchange (636C/T) was detected in exon 2 of the TASK-3 coding region. No evidence for an allelic association was found between the exon 2 polymorphism and absence epilepsy. Accordingly, genetic variation of the TASK-3 coding region does not play a major role in the etiology of idiopathic absence epilepsies.

Adolescent↗
PubMed2002

A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions.

CONTEXT: Missense mutations in the GABRG2 gene, which encodes the gamma 2 subunit of central nervous gamma-aminobutyric acid (GABA)(A) receptors, have recently been described in 2 families with idiopathic epilepsy. In one of these families, the affected individuals predominantly exhibited childhood absence epilepsy and febrile convulsions. OBJECTIVE: To assess the role of GABRG2 in the genetic predisposition to idiopathic absence epilepsies. DESIGN: The GABRG2 gene was screened by single-strand conformation analysis for mutations. Furthermore, a population-based association study assessing a common exon 5 polymorphism (C588T) was carried out. PATIENTS: The sample was composed of 135 patients with idiopathic absence epilepsy and 154 unrelated and ethnically matched controls. RESULTS: A point mutation (IVS6 + 2T-->G) leading to a splice-donor site mutation in intron 6 was found. The mutation, which is predicted to lead to a nonfunctional protein, cosegregates with the disease status in a family with childhood absence epilepsy and febrile convulsions. The association study did not find any significant differences in the allele and genotype frequencies of the common exon 5 polymorphism (C588T) between patients with idiopathic absence epilepsy and controls (P>.35). CONCLUSIONS: Our study identified a splice-donor-site mutation that was probably causing a nonfunctional GABRG2 subunit. This mutation occurred in heterozygosity in the affected members of a single nuclear family, exhibiting a phenotypic spectrum of childhood absence epilepsy and febrile convulsions. The GABRG2 gene seems to confer a rare rather than a frequent major susceptibility effect to common idiopathic absence epilepsy syndromes.

Adolescent↗
PubMed2002

Linkage analysis between childhood absence epilepsy and genes encoding GABAA and GABAB receptors, voltage-dependent calcium channels, and the ECA1 region on chromosome 8q.

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy (IGE) characterised by onset of typical absence seizures in otherwise normal children of school age. A genetic component to aetiology is well established but the mechanism of inheritance and the genes involved are unknown. Available evidence suggests that mutations in genes encoding GABA receptors or brain expressed voltage-dependent calcium channels (VDCCs) may underlie CAE. The aim of this work was to test this hypothesis by linkage analysis using microsatellite loci spanning theses genes in 33 nuclear families each with two or more individuals with CAE. Seventeen VDCC subunit genes, ten GABA(A)R subunit genes, two GABA(B) receptor genes and the ECA1 locus on 8q24 were investigated using 35 microsatellite loci. Assuming locus homogeneity, all loci gave statistically significant negative LOD scores, excluding these genes as major loci in the majority of these families. Positive HLOD scores assuming locus heterogeneity were observed for CACNG3 on chromosome 16p12-p13.1 and the GABRA5, GABRB3, GABRG3 cluster on chromosome 15q11-q13. Association studies are required to determine whether these loci are the site of susceptibility alleles in a subset of patients with CAE.

Calcium Channels↗
PubMed2002

Failure to replicate an allelic association between an exon 8 polymorphism of the human alpha(1A) calcium channel gene and common syndromes of idiopathic generalized epilepsy.

The present replication study tested the validity of a previously reported allelic association between a single nucleotide polymorphism in exon 8 (SNP8) of the gene encoding the alpha(1A)-calcium channel subunit (CACNA1A) and common subtypes of idiopathic generalized epilepsy (IGE). Pyrosequencing was applied to assess the SNP8 genotypes in 354 unrelated German IGE probands, both parents of 118 IGE probands, and 186 healthy control subjects of German descent. Our population-based association analysis did not provide evidence for an allelic association of SNP8 with either IGE or two phenotypically more homogeneous IGE subtypes, consisting of either 139 probands with juvenile myoclonic epilepsy or 207 probands whose IGE started with typical absence seizures (P>0.72). In addition, the transmission disequilibrium test did not indicate a preferential transmission of SNP8 alleles in 97 informative parent-child transmissions (McNemar chi(2)=0.093, df=1, P=0.76). Accordingly, we failed to confirm previous evidence that genetic variation of the CACNA1A gene confers susceptibility to common IGE syndromes.

Alleles↗
PubMed2002

Association of the 867Asp variant of the human anion exchanger 3 gene with common subtypes of idiopathic generalized epilepsy.

Genetic factors play a major role in the etiology of idiopathic generalized epilepsies (IGE). Our recent genome-wide search revealed suggestive evidence for a susceptibility locus for common IGE syndromes in the chromosomal region 2q36. The gene encoding the anion exchanger isoform 3 (AE3; gene symbol: SLC4A3) has been mapped to this candidate region. AE3 is prominently expressed in the brain and performs an electroneutral exchange of chloride and bicarbonate. To study the potential role of AE3 in the epileptogenesis of IGE, we performed a mutation analysis of the AE3 coding region, including the adjacent exon/intron boundaries, and the 5'-untranslated region in 16 IGE probands of families linked to chromosome 2q36 (cumulative two-point lod score: Z=5.32 at D2S371). Three exonic sequence variants were found: exon 17: 2600C/A, Ala867Asp; exon 21: 3391C/T, Leu1131Leu; exon 23: 3771G/A, 3'-UTR. Our subsequent population-based association study of the Ala867Asp substitution polymorphism revealed a significant increase of the 867Asp variant in 366 unrelated German IGE patients compared with 183 German control subjects (chi(2)=5.37, df=1, P=0.021). Consistently, the transmission disequilibrium test (TDT) of 121 parent-child trios showed a significant preferential transmission of the 867Asp allele (McNemar chi(2)=5.81, df=1, P=0.016). Our results support the hypothesis that variation of the AE3 gene confers a common but small susceptibility effect to the etiology of a broad spectrum of IGE syndromes.

Alleles↗