Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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In the present study, we evaluated the possible contribution of genetic variation of the serotonin 5-HT7 receptor to the development of schizophrenia and bipolar affective disorder. Cloning and characterization of exon-flanking intronic sequences enabled us to investigate the whole coding region and the exon-intron boundaries of the human 5-HT7 receptor gene. Using single-strand conformational analysis, we screened for presence of DNA sequence variation in a sample of 137 unrelated individuals including 45 schizophrenic and 46 bipolar affective patients, as well as 46 healthy controls. We detected two rare naturally occurring receptor variants (Pro-279-Leu, Thr-92-Lys) and a silent nucleotide substitution (A-->G) at position +1233. The occurrence of the Pro-279-Leu and Thr-92-Lys substitutions was studied in an extended sample of patients (n = 462) and controls (n = 335). The Leu-279 variant was found in similar frequency in all groups, indicating that presence of this variant is not causally related to the development of schizophrenia or bipolar affective disorder. The Lys-92 variant was found in a single individual who suffered from bipolar affective disorder. Investigation of the patient's family revealed independent segregation between the Lys-92 variant and psychiatric illness. Our data suggests that genetic variation of the 5-HT7 receptor does not play a major role in the development of bipolar affective disorder and schizophrenia.
Mol Psychiatry 1996 Nov
PMID:The human serotonin 7 (5-HT7) receptor gene: genomic organization and systematic mutation screening in schizophrenia and bipolar affective disorder. 915 33

Bipolar disorder affects approximately 1% of the population and there is evidence that genetic factors play an important role in the production of symptoms. We undertook a genetic linkage study for the discovery of a major locus conferring susceptibility for bipolar illness in an Old Order Amish pedigree. Our study took advantage of publicly available phenotypic and genotypic information, the latter as a byproduct of the human genome project effort. We present a genomic scan using 1772 polymorphic genetic markers and we suggest candidate genetic regions for harboring a bipolar disorder susceptibility gene.
Mol Psychiatry 1996 Nov
PMID:Scanning the genome with 1772 microsatellite markers in search of a bipolar disorder susceptibility gene. 915 35

Both mania and bipolar depression have been associated with decrements in the activity of the sodium and potassium-activated adenosine triphosphatase (Na,K-ATPase) membrane pump. Although the role of this observation in the pathophysiology of bipolar illness is unclear, it has been proposed that this defect could be central to the pathogenesis of the illness. In an effort to test this hypothesis, the authors examined the efficacy of lithium pretreatment in attenuating behavioral changes secondary to acute administration of a single intracerebroventricular (i.c.v.) dose of the Na,K-ATPase-inhibiting compound, ouabain, in the Sprague-Dawley rat. Ouabain (10(-3)M) significantly decreased motor activity in automated activity monitors. Lithium pretreatment for 7 d totally prevented this effect. These preliminary data suggest that i.c.v. ouabain administration in the rat may prove to be a viable animal model for bipolar illness.
Mol Chem Neuropathol 1997 May
PMID:Lithium prevents ouabain-induced behavioral changes. Toward an animal model for manic depression. 927 Oct 6

Inositol monophosphatase is a key enzyme in the de novo biosynthesis of inositol and in the phosphoinositide second-messenger signalling pathway. Inhibition of this enzyme is a proposed mechanism for lithium's pharmacological action in bipolar illness (manic depression). Very little is known about how expression of this enzyme is regulated. Because the yeast Saccharomyces cerevisiae has been shown to be an excellent model system in which to understand the regulation of inositol metabolism, we characterized inositol monophosphatase in this yeast. Lithium inhibited monophosphatase activity in vitro. Growth in the presence of inositol resulted in increased expression of the enzyme in vivo, although inositol had no effect on enzyme activity in vitro. The inositol effect was apparent when cells were grown in glucose but not in glycerol/ethanol. Monophosphatase activity was derepressed as cells entered stationary phase. This effect was apparent only during growth in glucose plus inositol. The results demonstrate that S. cerevisiae monophosphatase is inhibited by lithium and regulated by factors affecting phospholipid biosynthesis.
Mol Microbiol 1997 Aug
PMID:Regulation of inositol monophosphatase in Saccharomyces cerevisiae. 930 16

There are currently 13 diseases known to be caused by unstable triplet repeat mutations; however, there are some instances (as with FRAXF and FRA16) when these mutations appear to be asymptomatic. In a search for polymorphic CTG repeats as candidate genes for bipolar disorder, we screened a genomic human chromosome 18-specific library and identified a 1.6 kb clone (7,6A) with a CTG24 repeat that maps to 18q21.1. The CTG repeat locus, termed CTG18.1, is located within an intron of human SEF2-1, a gene encoding a basic hellx-loop-hellx DNA binding protein involved in transcriptional regulation. The CTGn repeat is highly polymorphic and very enlarged alleles, consistent with expansions of up to CTG2100, were identified. PCR and Southern blot analysis in pedigrees ascertained for a Johns Hopkins University bipolar disorder linkage study and in CEPH reference pedigrees revealed a tripartite distribution of CTG18.1 alleles with stable alleles (CTG10-CTG37), moderately enlarged and unstable alleles (CTG53-CTG250), and very enlarged, unstable alleles (CTG800-CTG2100). Moderately enlarged alleles were not associated with an abnormal phenotype and have a combined enlarged allele frequency of 3% in the CEPH and bipolar populations. Very enlarged alleles, detectable only by Southern blot analysis of genomic digests, have thus far been found in only three individuals from our bipolar pedigrees, and to date, have not been found in any of the CEPH reference pedigrees. These enlarged alleles may arise, at least in part, via somatic mutation.
Hum Mol Genet 1997 Oct
PMID:A novel, heritable, expanding CTG repeat in an intron of the SEF2-1 gene on chromosome 18q21.1. 930 63

Within the broad susceptibility region for bipolar disorder on the pericentromeric portion of chromosome 18, the highest allele sharing in our 22-pedigree series has been found in markers mapping to 18p11.2. Studies by other investigators on independently ascertained pedigrees have also shown increased sharing in this region, making 18p11.2 a plausible site for a candidate gene search. We found expressed sequence tags (ESTs) mapping within this area that are homologous to the myo-inositol-1-phosphate phosphohydrolase (myo-inositol monophosphatase: IMP) gene of Xenopus laevis. Since IMP has been proposed to be the potential target of lithium, a drug commonly used for the treatment of bipolar disorder, we proceeded to characterize the cognate transcript. Northern blot analysis detected a major transcript of 1.5 kb with abundant expression in adult and fetal tissues, but minimal expression in whole brain. In subcortical brain regions, however, substantial levels of transcript were evident, most prominently in the caudate. We have isolated and sequenced the full-length cDNA. The deduced amino acid sequence revealed approximately 54% identity with an existing human IMP, which we found mapped to chromosome 8, and IMP of other species. The sequence also included motifs characteristic of the IMP gene family. To provide a more precise location of this gene, mapping with a panel of radiation hybrids (RH) was conducted. Multipoint RH analysis placed the gene between GNAL and D18S71 within the 18p11.2 region. We, therefore, designated this novel gene as IMP.18p. The physical position and possible function suggest that IMP.18p is an important candidate gene for bipolar disorder.
Mol Psychiatry 1997 Sep
PMID:A novel human myo-inositol monophosphatase gene, IMP.18p, maps to a susceptibility region for bipolar disorder. 932 33

The human serotonin transporter gene (hSERT) is a strong candidate for involvement in the pathogenesis of mood disorder and, using a UK Caucasian case-control sample, Collier et al found a significant association between bipolar disorder and the 12 allele of the VNTR polymorphism in intron 2 of this gene. In a European collaborative sample, Collier et al found a significant association between affective disorder and a functional deletion polymorphism in the promoter of hSERT. We have undertaken association studies using these polymorphisms in a British Caucasian sample comprising 171 DSM-IV bipolar probands, 80 DSM-IV major depression probands and 121 unrelated controls matched to bipolar probands for age, sex and ethnicity. We found no association between the promoter deletion and affective disorder but our findings with the VNTR polymorphism are similar to those of Collier and colleagues: we found a significant excess of the 12 repeat allele in bipolar probands (P = 0.031, one-tall) with a suggestion of a gene dosage effect (using genotypes bearing no 12 repeat allele as baseline, the increased risks conferred by genotypes bearing 12 repeat alleles were: heterozygote, OR = 1.24; homozygote, OR = 1.76). Our findings add to the evidence that variation at or near hSERT influences susceptibility to bipolar disorder in the British Caucasian population.
Mol Psychiatry 1997 Sep
PMID:Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT). 932 34

There is some evidence suggesting that a polymorphism of variable number of tandem repeats (VNTR) in the second intron of the serotonin transporter (5-HTT) gene and another variation which lies 1.2 kb upstream of the promoter of the gene (5-HTTLPR) are associated with affective disorders. However, conflicting results have also been reported. We examined an allelic association of these two polymorphisms in a Japanese sample of 191 patients with affective disorders (142 bipolar and 49 unipolar) and 212 controls. Substantial differences in the number and frequency of alleles between Caucasians and Japanese were observed for both polymorphisms. A significant association between the VNTR polymorphism and bipolar disorder (genotypic association: odds ratio 2.2, 95% CI 1.2-4.0; allelic association: odds ratio 1.7, 95% CI 1.0-3.0) was found, but not between the 5-HTTLPR polymorphism and bipolar disorder. No significant association with unipolar depression was detected using either genetic marker, although this may be attributable to the relatively small number of subjects with unipolar depression. Our results suggest that the VNTR itself or another unknown functional polymorphism which would be in linkage disequilibrium to the VNTR has an effect on susceptibility to bipolar disorder.
Mol Psychiatry
PMID:Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. 939 88

Several recent studies have suggested that expanded CAG repeats may contribute to the genetic transmission of bipolar disorder and schizophrenia. In all known disorders associated with expanded CAG repeats, the repeat sequence is translated into glutamine. Therefore the simplest hypothesis is that one or more proteins with expanded polyglutamine sequences are involved in the pathogenesis of bipolar disorder and schizophrenia. In order to examine this hypothesis, we have used an antibody against expanded polyglutamine sequences to examine Western blots prepared from lymphoblastoid cell lines of patients with schizophrenia and bipolar disorder. We also examined Western blots prepared from left frontal cortex tissue samples obtained from 11 schizophrenics post mortem. With the exception of the TATA-binding protein (TBP), we did not detect any proteins containing expanded polyglutamine sequences. Our data therefore suggest either that the expanded repeats which are associated with these disorders do not encode polyglutamine, or that they are within genes that are not expressed within the tissues investigated here.
Mol Psychiatry
PMID:No evidence for expanded polyglutamine sequences in bipolar disorder and schizophrenia. 939 91

Corticotropin-releasing hormone (CRH) plays a key role in the regulation of the stress response. Abnormalities in CRH secretion have been documented in both the depression and manic phases of bipolar disorder (BPD). In the present study, we investigated genetic linkage between the CRH gene and BPD in 22 pedigrees. A highly informative, short tandem repeat (STR) polymorphism adjacent to the CRH gene on human chromosomal region 8q13 was used to examine linkage. Affected sibling pair (ASP) and the likelihood-based disequilibrium tests revealed nonsignificant values. We conclude that the CRH gene is not linked to BPD; if genes involved in the regulation of stress response are indeed linked to BPD, the search should be directed towards those that regulate CRH secretion or its effects on target tissues.
Mol Psychiatry
PMID:Lack of linkage between the corticotropin-releasing hormone (CRH) gene and bipolar affective disorder. 939 92


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