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D B Wildenauer

Publications and source records attributed to D B Wildenauer.

At least 37 records · Page 2Linked to original sources
PubMed1999

Family and genetic studies on the relationship of schizophrenia to affective disorders.

Schizophrenia is a genetically influenced disease with a broad and heterogeneous phenotype transmitted in families. Of particular interest is the familial-genetic relationship between schizophrenia and affective disorders. Taking advantage of refined epidemiological methods, the dichotomy between both groups of disorders is not less consistently found than expected. Recently, linkage studies identified multiple candidate regions for susceptibility genes for each of both disorders. Several of these candidate regions for schizophrenia are overlapping with candidate regions for bipolar disorder. Thus, the hypothesis of an etiological dichotomy of schizophrenia and affective disorders faces a new challenge.

Chromosome Aberrations↗
PubMed1999

Association between hSKCa3 and schizophrenia not confirmed by transmission disequilibrium test in 193 offspring/parents trios.

A possible association between the small conductance calcium-regulated potassium channel gene, hSKCa3, and schizophrenia has recently been described by Chandy et al using a case-control design with patients with schizophrenia (n=141) and matched controls (n = 158). The gene may be considered as an excellent candidate gene for psychiatric disorders, since it plays a role in modulating neuronal firing patterns by regulating the slow component of after hyperpolarisation. In addition, the gene contains a highly polymorphic trinucleotide sequence (CAG) within exon 1, which encodes a polyglutamine stretch. The possible contribution of unstable trinucleotide repeats to the development of psychiatric disorders has previously been discussed. Chandy et al reported an over-representation of alleles with higher repeat number in schizophrenics as compared to controls (P = 0.0035). In an attempt to replicate these findings, we have performed a family-based study with 193 offspring/parent combinations using a sample of 49 multiplex families (two or more affected siblings with parents) and a second sample of 83 simplex families (one affected offspring with parents). No evidence for the association of longer repeats with schizophrenia was obtained when each sample was tested separately or when both samples were combined and tested for transmission disequilibrium.

Female↗
PubMed1998

Further evidence for a susceptibility locus on chromosome 10p14-p11 in 72 families with schizophrenia by nonparametric linkage analysis.

Recent reports on potential linkage by Faraone and the NIMH Genetics Initiative-Millennium Schizophrenia Consortium [1997: Am J Med Genet 74:557], and by Straub et al. [1997: Am J Med Genet 74:558], prompted us to study chromosome 10 in a sample of 72 families containing 2 or more affected sibs with schizophrenia for additional evidence of linkage. We obtained highest allele sharing for the two markers D10S582 (61.5% allele sharing, chi2 = 7.6, P = 0.0058) and D10S1423 (59% allele sharing, chi2 = 4.76, P = 0.029). D10S1423 is one of the markers with the highest lod scores in the study of Faraone and the NIMH Genetics Initiative-Millennium Schizophrenia Consortium [1997: Am J Med Genet 74:557]. GENEHUNTER analysis revealed a nonparametric lod score (NPL) of 3.2 (P = 0.0007) for the marker D10S1714, which lies in the same region. Multipoint affected sib-pair lod score analysis (identity by descent) calculated by ASPEX revealed a lod score of 1.72 for all possible sib-pair combinations (107) and of 2.13, when only independent sib-pairs (87) were counted. Our study provides further evidence for a potential susceptibility locus for schizophrenia on chromosome 10p.

Alleles↗
PubMed1998

Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis.

The action of antipsychotic drugs on dopamine receptors suggests that dopaminergic signal transmission may play a role in the development of schizophrenia. We tested eight candidate genes (coding for dopamine receptors, the dopamine transporter, and G-proteins) in 59 families from Germany and Israel, for association. A P value of .00055 (.0044 when corrected for the no. of markers tested) was obtained for the intronic CA-repeat marker G-olfalpha on chromosome 18p. The value decreased to .000088 (.0007) when nine sibs with recurrent unipolar depressive disorder were included. Linkage analysis using SSLP markers densely spaced around G-olfalpha yielded a maximum two-point LOD score of 3.1 for a marker 0.5 cM distal to G-olfalpha. Multipoint analysis under the assumption of heterogeneity supported this linkage-whether the affected pheotype was defined narrowly or broadly-as did nonparametric linkage (NPL). In 12 families with exclusively maternal transmission of the disease, the NPL value also supported linkage to this marker. In order to test for association/linkage disequilibrium in the presence of linkage, the sample was restricted to independent offspring. When this sample was combined with 65 additional simplex families (each of them comprising one schizophrenic offspring and his or her parents), the 124-bp allele of G-olfalpha was transmitted 47 times and was not transmitted 21 times (P=.009). These results suggest the existence, on chromosome 18p, of a potential susceptibility locus for functional psychoses.

Chromosomes, Human, Pair 18↗
PubMed1997

Evidence suggestive of a locus on chromosome 5q31 contributing to susceptibility for schizophrenia in German and Israeli families by multipoint affected sib-pair linkage analysis.

Suggestive evidence for a potential susceptibility locus for schizophrenia at 5q31 was obtained in two family samples. Sample I consisted of 14 families with schizophrenia and revealed for the marker IL9 a lod score of 1.8 by two point lod score analysis. Sample II comprised 44 families including four from sample I and was ascertained in order to employ affected sib-pair analysis by identity by descent. A lod score of 1.8 around the marker D5S399 was obtained by multipoint analysis. The lod score remained positive, but decreased to 1.27 when the four families from sample I were excluded in order to use sample II as a statistically independent replication sample. We propose a susceptibility locus for schizophrenia with probably minor contribution in the pedigrees under investigation.

Chromosomes, Human, Pair 5↗
PubMed1996

Genetic relationship between dopamine transporter gene and schizophrenia: linkage and association.

This study explores the genetic relationship between schizophrenia and the dopamine transporter gene (DAT) by a variety of methods. In a sample of 48 families--each family containing at least one nuclear family with a pair of affected siblings--we performed linkage analysis using the maximum likelihood (LOD score) method as well as sibpair analysis (identity by descent). In addition, we investigated a sample of 108 nuclear families--index case affected with schizophrenia/chronic schizoaffective disorder--for association using the haplotype relative risk method. Linkage between schizophrenia and DAT using two- and three-point linkage analysis was excluded with all disease models employed. No evidence for association between haplotypes of the VNTR-probe of the DAT and schizophrenia has been detected. Thus, a contribution of the DAT gene to the genetic diathesis of schizophrenia is unlikely in the families studied.

Adult↗
PubMed1994

No evidence of linkage between the dopamine D2 receptor gene and schizophrenia.

The antipsychotic effects of dopamine D2 receptor antagonists (neuroleptics) and the psychotomimetic effects of dopamine agonists suggest that a defect of the D2 receptor gene might be a factor in the etiology of schizophrenia. Fifteen families that contained several members suffering from schizophrenia were tested for linkage between the D2 receptor gene and schizophrenia. In addition, four flanking markers were tested. The mode of inheritance was assumed to be dominant. Five different models of the affection status, which ranged from a narrow to a broad definition of the affection status, were studied. Linkage analysis was carried out with dominant, recessive, and intermediate modes of transmission. Two-point and multipoint analyses between schizophrenia and the D2 receptor gene resulted in log-likelihood differences < -2 for all five models, and linkage between this candidate gene and schizophrenia was excluded. A mutation in the D2 receptor gene itself is therefore extremely unlikely to be related to a higher susceptibility to schizophrenia, at least in the present group of families.

Bipolar Disorder↗
PubMed1986

The interactions of mesna and dimesna with the sulfate exchange in human red blood cells.

The influence of disodium 2-mercaptoethane sulfonate disulfide (mesna, Uromitexan) and sodium 2-mercaptoethane sulfonate (dimesna) on the carrier mediated exchange of 35S-sulfate in human red blood cells was investigated in vitro in order to contribute to the understanding of pharmakokinetics and organospecific action of mesna. Countertransport indicated uptake of mesna in washed red blood cells by the carrier. In contrast, dimesna inhibited the transport of sulfate in a competitive manner. However, when 35S-sulfate uptake into red cells was studied with whole blood, addition of mesna was found to be inhibitory, which was caused by its rapid conversion to dimesna by plasma components. It is concluded that conversion of the anion carrier substrate mesna into the inhibitor dimesna is the reason that mesna or dimesna cannot be detected in red blood cells in vivo.

Erythrocytes↗
PubMed1983

Solubility of phenothiazines in red blood cell membranes as evidenced by photoaffinity labeling.

Radioactively labeled 7-azido-fluphenazine and 7-azido-triflupromazine methiodide have been synthesized and their binding to membranes of intact red blood cells and to ghosts was compared after irradiation. The results indicated that tertiary phenothiazines react with integral membrane components. We conclude from the results that amphiphilic substances solubilize in biological membranes. This is in contradiction to the proposal that these compounds are excluded from the hydrophobic core of biological membranes (Conrad & Singer (1979) Proc.Natl.Acad.Sci.U.S.A. 76, 5202-5206 and (1981) Biochemistry 20, 808-818).

Affinity Labels↗
PubMed1982

Interaction of cyclophosphamide metabolites with membrane proteins: an in vitro study with rabbit liver microsomes and human red blood cells. Effect of thiols.

Cyclophosphamide metabolites have been generated in vitro by microsomal oxidation of cyclophosphamide and their binding to rabbit liver microsomes and to intact human red blood cells has been investigated. Reactions with proteins of membrane and cytoplasm were detected by SDS polyacrylamide gel electrophoresis. The protein bands were analysed for incorporation of radioactivity. The following results were obtained. (1) Preferential binding of acrolein to microsomes and erythrocytes, with only little binding of metabolites containing the chloroethyl moiety. (2) Reduction of acrolein binding by the thiol compounds glutathione, 2,3-dimercaptopropane-1-sulfonate and mercaptoethane sulfonate. (3) In microsomes: formation of protein polymerisation products and incorporation of radioactivity. (4) In red blood cells: cross-linking of membrane proteins and formation of globin dimerization products in the cytoplasm.

Acrolein↗
PubMed1982

Interactions of the chelating agent 2,3-dimercaptopropane-1-sulfonate with red blood cells in vitro. I. Evidence for carrier mediated transport.

Uptake of the water soluble 1,2-dimercaptopropanol (BAL) derivative 2,3-dimercapto-1-sulfonate (DMPS) into human red blood cells was found in vitro and the mode of penetration studied in detail. The compound entered erythrocytes in a concentration dependent manner. In contrast to sealed ghosts where inside and outside concentrations reached the same value, DMPS accumulated in intact erythrocytes. Since no binding of DMPS could be detected, the reason for accumulation was assumed to be a conversion of DMPS into chelates or metabolites which penetrated the membrane in a slower rate. A facilitated transport of DMPS mediated by the anion carrier protein was concluded on the basis of the following similarities with the anion transport: inhibition of [14C]DMPS-uptake by N-ethylmaleimide (NEM), tetrathionate (90%), sulfate (50%), 5,5'-dithio bis(2-nitrobenzoic acid) (DTNB) (25%); inhibition of uptake and efflux by 4,4'-diisothiocyano-2,2'-stilbene disulfonate (DIDS) (80%), dipyridamole (55%); temperature dependency (activation energy 24 Kcal/mol); pH-dependency (pH optimum about 6.9); counter-transport; activation of uptake by preincubation with DMPS (transmembrane effect).

Cell Membrane↗
PubMed1982

Interactions of the chelating agent 2,3-dimercaptopropane-1-sulfonate with red blood cells in vitro. II. Effects on metalloproteins.

The implications of the carrier mediated uptake of 2,3-dimercaptopropane-1-sulfonate (DMPS) (D.B. Wildenauer et al., Chem.-Biol. Interact., 42 (1982) 165) on cytoplasmic components of human red blood cells have been investigated in vitro. The water-soluble chelating agent caused a mobilization of metals (zinc and copper) from metalloproteins which resulted in a permeation of the membrane. Furthermore, a cytoplasmic protein was found to be attached to the membrane after DMPS treatment of red blood cells. The protein was isolated and identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), amino acid analysis and finger-printing as carbonic anhydrase. The enzyme could be solubilized from the membrane by addition of beta-mercaptoethanol, suggesting an involvement of sulfhydryl-groups. In a reconstitution experiment, DMPS-treated human carbonic anhydrase could be attached to inside-out vesicles which were prepared from human erythrocytes. In contrast, bovine carbonic anhydrase, which is known to lack sulfhydryl-groups, failed to bind to the same vesicles. Moreover, attachment of carbonic anhydrase to the membrane did not occur when intact bovine erythrocytes were treated with DMPS. It is suggested that zinc-depletion of carbonic anhydrase causes the liberation of a sulfhydryl-group of the enzyme. This is followed by a disulfide formation with a component of the membrane which results in the observed membrane attachment.

Amino Acids↗