Biomedical subjects
S Cichon
Publications and source records attributed to S Cichon.
Association study of a null mutation in the dopamine D4 receptor gene in Italian patients with obsessive-compulsive disorder, bipolar mood disorder and schizophrenia.
Although serotonergic dysregulation is a leading pathogenetic hypothesis for obsessive-compulsive disorder (OCD), some evidence also suggests a possible dysregulation of the dopaminergic system in this disorder. Therefore, individual differences in deoxyribonucleic acid (DNA) coding for dopamine receptor proteins might contribute to the genetic background of this disorder. Previously we reported a null mutation in exon 1 of the dopamine D4 receptor gene. The variant type is characterized by a 13 bp deletion and is predicted to code for a truncated, non-functional receptor. We assessed the frequency of this polymorphism in 157 OCD patients, 196 schizophrenics, 111 bipolars and 162 healthy controls of Italian descent. Our findings do not implicate a role for this mutation in conferring a susceptibility to OCD and confirm previous negative results regarding its involvement in schizophrenia and bipolar disorder.
The human complement C8G gene, a member of the lipocalin gene family: polymorphisms and mapping to chromosome 9q34.3.
Complement component C8 is a plasma glycoprotein consisting of three nonidentical polypeptide chains (alpha, beta, gamma) which are encoded by three separate genes (C8A, C8B, C8G). The gamma chain whose functional role remains undefined is not related to any other complement protein but is a member of the lipocalins, a family of proteins that bind small hydrophobic ligands. The present report describes the first known polymorphisms for the human C8G gene, namely one polymorphic site in exon 1 (207T/G) and two polymorphic sites in intron 1 (213 + 37G --> A; 213 + 65del3). Specific typing can be performed using simple polymerase chain reaction-based assays. C8G genotyping in eight CEPH reference families demonstrated that C8G is closely linked to a series of marker loci located in the most telomeric region of chromosome 9q. Multipoint analysis placed C8G with 1000:1 support distal to D9S207. C8G is thus located at 9q34.3. Remarkably, this chromosomal region contains at least four other lipocalin genes.
Systematic screening for mutations in the promoter and the coding region of the 5-HT1A gene.
In the present study we sought to identify genetic variation in the 5-HT1A receptor gene which through alteration of protein function or level of expression might contribute to the genetic predisposition to neuropsychiatric diseases. Genomic DNA samples from 159 unrelated subjects (including 45 schizophrenic, 46 bipolar affective, and 43 patients with Tourette's syndrome, as well as 25 healthy controls) were investigated by single-strand conformation analysis. Overlapping PCR (polymerase chain reaction) fragments covered the whole coding sequence as well as the 5' untranslated region of the 5-HT1A gene. The region upstream to the coding sequence we investigated contains a functional promoter. We found two rare nucleotide sequence variants. Both mutations are located in the coding region of the gene: a coding mutation (A-->G) in nucleotide position 82 which leads to an amino acid exchange (Ile-->Val) in position 28 of the receptor protein and a silent mutation (C-->T) in nucleotide position 549. The occurrence of the Ile-28-Val substitution was studied in an extended sample of patients (n = 352) and controls (n = 210) but was found in similar frequencies in all groups. Thus, this mutation is unlikely to play a significant role in the genetic predisposition to the diseases investigated. In conclusion, our study does not provide evidence that the 5-HT1A gene plays either a major or a minor role in the genetic predisposition to schizophrenia, bipolar affective disorder, or Tourette's syndrome.
Identification of two novel polymorphisms and a rare deletion variant in the human dopamine D4 receptor gene.
We report two novel polymorphisms and a rare deletion variant in the human dopaine D4 receptor gene. The two polymorphisms are characterized by single base pair substitutions, namely a G-->C transversion changing codon 11 from GGG (encoding Gly) to CGG (encoding Arg) and a C-->T transition in position -11 upstream from the start codon. The Arg11 variant occurs at a frequency of about 1% and the C-->T transition at a frequency of about 7% in German control subjects (n = 148). Allele frequencies observed in patients suffering from schizophrenia (n = 256) and bipolar affective disorder (n = 99) were similar. The deletion variant is characterized by a 21 bp deletion affecting codons 36 to 42 coding for amino acids Ala-Ala-Leu-Val-Gly-Gly-Val located in the first transmembrane domain of the dopamine D4 receptor. The mutation was identified in a single individual suffering from obsessive-compulsive disorder and panic disorder. We were unable to detect the deletion in patients with schizophrenia and bipolar affective disorder, nor in healthy controls.
Single-strand conformation analysis (SSCA) of the dopamine D1 receptor gene (DRD1) reveals no significant mutation in patients with schizophrenia and manic depression.
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Association analysis of the dopamine D2 receptor gene in Tourette's syndrome using the haplotype relative risk method.
Comings et al. [1991: JAMA 266: 1793-1800] have recently reported a highly significant association between Tourette's syndrome (TS) and a restriction fragment length polymorphism (RFLP) of the dopamine D2 receptor gene (DRD2) locus. The A1 allele of the DRD2 Taq I RFLP was present in 45% of the Tourette patients compared with 25% of controls. We tried to replicate this finding by using the haplotype relative risk (HRR) method for association analysis. This method overcomes a major problem of conventional case-control studies, where undetected ethnic differences between patients and controls may result in a false-positive finding, by using parental alleles not inherited to the proband as control alleles. Sixty-one nuclear families encompassing an affected child and parents were typed for the DRD2 Taq I polymorphism. No significant differences in DRD2 A1 allele frequency were observed between TS probands, subpopulations of probands classified according to tic severity, or parental control alleles. Our data do not support the hypothesis that the DRD2 locus may act as a modifying gene in the expression of the disorder in TS probands.
Dopamine D2 receptor molecular variant and schizophrenia.
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Detection of four polymorphic sites in the human dopamine D1 receptor gene (DRD1).
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Human dopamine D4 receptor gene: frequent occurrence of a null allele and observation of homozygosity.
We report a null mutation in the first exon of the human dopamine D4 receptor (DRD4) gene. The mutation is predicted to result in a truncated non-functional protein and is the first natural nonsense mutation found in a human dopamine receptor gene. It occurs with a frequency of about 2% in the general population. The distribution of the mutation was found to be similar in healthy controls and patients suffering from psychiatric diseases which included schizophrenia, bipolar affective disorder and Tourette's syndrome, indicating that heterozygosity for this mutation in the DRD4 gene is not causally related to major psychiatric diseases. We also identified an adult male who is homozygous for this mutation. He shows no symptoms of major psychiatric illness, but he displays somatic ailments including acousticous neurinoma, obesity and some disturbances of the autonomic nervous system. Some of these symptoms might be related to the absence of functional DRD4 protein.
Polymorphism of human complement component C6: an amino acid substitution (Glu/Ala) within the second thrombospondin repeat differentiates between the two common allotypes C6 A and C6 B.
Component C6 of the human complement system exhibits a genetic polymorphism in all populations tested so far. Using isoelectric focusing two common allotypes, C6 A ('acidic') and C6 B ('basic') and a number of rare variants have been described. A comparison of the two published cDNA sequences of C6 suggests a polymorphism in codon 98. Using polymerase chain reaction (PCR) we amplified a segment of the human C6 gene encompassing the presumably polymorphic codon. According to the restriction fragment patterns obtained after DdeI digestion of the PCR product, three genotypes were distinguished. The polymorphism is caused by a nucleotide substitution (C-->A) in the second position of codon 98; allele 1 (GCG) codes for Ala, allele 2 (GAG) for Glu. Sequencing of PCR products confirmed the mutation. For 46 unrelated individuals genotyped by this PCR-based method we also determined C6 protein phenotype. Three phenotypes were observed (C6 A, C6 AB, C6 B). There was an absolute concordance between C6 protein typing and DNA typing. We thus conclude that the C6 A allotype is characterized by a Glu and the C6 B allotype by an Ala residue in position 98 of the C6 polypeptide chain.
A serine to glycine substitution at position 9 in the extracellular N-terminal part of the dopamine D3 receptor protein: no role in the genetic predisposition to bipolar affective disorder.
Association studies offer a promising tool to investigate the potential role of DNA sequence variation affecting the expression or sequence of proteins in susceptibility to common diseases. We determined the frequency of a DNA polymorphism resulting in a glycine to serine substitution at position 9 in the extracellular N-terminal part of the dopamine D3 receptor protein in a sample of 83 patients suffering from bipolar affective disorder and 100 control subjects. No significant differences between the groups were found. Thus, this substitution, which is the first sequence variation identified in the dopamine D3 receptor gene altering the amino acid sequence of the protein, can be regarded as a protein variant with no major effect on the susceptibility to bipolar affective disorder.
Excess of homozygosity at the dopamine D3 receptor gene in schizophrenia not confirmed.
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Pseudoautosomal marker DXYS20 and manic depression.
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Association and linkage studies in bipolar affective disorder.
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Assignment of the human serotonin 4 receptor gene (HTR4) to the long arm of chromosome 5 (5q31-q33).
In the present study, we report the chromosomal localization of the human 5-HT4 receptor gene (HTR4) by the analysis of somatic cell hybrids. Based upon genomic sequences of the HTR4 gene, a primer set was selected that reacted with human genomic DNA but not mouse or hamster genomic DNA. Using monochromosomal hybrid cell lines of the NIGMS Mapping Panel 2 we localized the HTR4 gene to human chromosome 5. To confirm the localization on chromosome 5 and to further sublocalize the HTR4 gene, the radiation hybrid panel RH3 was similarly analysed. Significant linkage was obtained to genetic marker D5S2654. This localizes the HTR4 gene to human chromosome 5q31-q33.