Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several mapping studies of families with multiple individuals who have bipolar affective disorder (BPAD) have demonstrated possible linkage of the trait to the pericentric region of chromosome 18 (18cen). Currently, the large size of the critical interval defined by these studies makes effective selection of candidate genes formidable. However, documentation of 18cen-linked families in which a parent-of-origin effect was observed in the transmission of the BPAD trait provides a clue to the nature of the putative gene; it may be imprinted. In the present study, we cloned IMPACT, the human homolog of the mouse imprinted gene Impact and mapped it to 18cen within the critical interval for BPAD. Human IMPACT encodes a protein with 320 amino acids and is expressed at high levels in the brain. Since only a small number of imprinted genes are estimated to be present in the entire genome, very few imprinted genes would be expected to be present in this particular chromosomal region. Hence, IMPACT represents a candidate gene for BPAD susceptibility. Alternatively, other as yet unknown imprinted gene(s) adjacent to IMPACT could contribute to the BPAD trait, since multiple imprinted genes may occasionally form clusters. Localization of human IMPACT at 18cen in this study defines a promising target region in which to search for putative BPAD genes.
Mol Psychiatry 2001 Jan
PMID:Human homolog of the mouse imprinted gene Impact resides at the pericentric region of chromosome 18 within the critical region for bipolar affective disorder. 1124 91

Bipolar affective disorder is a genetically complex psychiatric disorder with a population prevalence of approximately 1%. We have previously reported cosegregation of bipolar affective disorder and Darier's disease, a dominant skin disorder with a neuropsychiatric component. The gene for Darier's disease was mapped to chromosome 12q23-q24.1 and linkage studies by us and others have subsequently implicated this region as harbouring a susceptibility gene for bipolar affective disorder. In this study we have investigated the Darier's disease gene ATP2A2, the calcium pumping ATPase SERCA2, as a potential susceptibility gene for bipolar disorder under the hypothesis that variations in SERCA2 have pleiotropic effects in brain. Support for this hypothesis comes from clinical evidence of neuropsychiatric abnormalities in Darier's disease, genetic data produced in our study showing non-random clustering of missense mutations in ATP2A2 in neuropsychiatric Darier patients, and functional data demonstrating the role of SERCA2 in intracellular calcium regulation. In a panel of 15 unrelated bipolar patients from multiply affected families showing increased allele sharing at markers in the 12q23-q24.1 region, we performed mutational screening of the ATP2A2 coding sequence, promoter regions, and 3' untranslated region and identified six sequence variations. These were analysed in a large sample of bipolar patients (n = 324) and control subjects (n = 327). Analysis of allele and genotype distributions for all six variations, and of haplotype frequencies showed no evidence for the involvement of ATP2A2 in producing susceptibility to bipolar disorder.
Mol Psychiatry 2001 Jan
PMID:Exclusion of the Darier's disease gene, ATP2A2, as a common susceptibility gene for bipolar disorder. 1124 92

Linkage studies indicate that chromosome 22q contains a locus, or loci, for schizophrenia (SZ) and bipolar disorder (BPD). Furthermore, the congenital disorder velo cardio facial syndrome (VCFS), which is usually caused by a 22q11 microdeletion, is associated with an increased prevalence of psychiatric disease, including SZ and BPD. One plausible candidate gene that maps to 22q11, in a region deleted in the most common form of VCFS, is SNAP29, a member of the SNAP-25 family of SNARE proteins. To search for possible functional mutations in SNAP29 that could be analyzed as candidates for 22q11-linked psychiatric problems, exons, intron-exon junctions and the promoter region were screened. No coding variants were found, although a silent mutation at codon 6 and three single nucleotide polymorphisms (SNPs) were identified in the 5' untranslated and promoter regions. One SNP, an A-->G transition 923 [corrected] nucleotides upstream of the transcription start site, showed a moderately significant difference in the distribution of alleles and genotypes in patients with SZ compared with controls (allele frequency: chi(2) = 5.57, 1 df, P = 0.018; genotype: chi(2) = 9.49, 2 df, P = 0.009; odds ratio = 1.59, 95% Cl = 1.08--2.34). No significant difference was found in patients with BPD. Although the functional significance of this mutation is not known, the tetranucleotide core sequence of the ets and IK2 families of transcription factors is altered as a result of the SNP. These data suggest that a mutation in the SNAP29 gene promoter region, or a mutation in linkage disequilibrium with the promoter SNP, may be involved in the pathogenesis of chromosome 22-linked SZ.
Mol Psychiatry 2001 Mar
PMID:Polymorphism in SNAP29 gene promoter region associated with schizophrenia. 1131 22

Preliminary clinical data indicate that omega-3 fatty acids may be effective mood stabilizers for patients with bipolar disorder. Both lithium and valproic acid are known to inhibit protein kinase C (PKC) activity after subchronic administration in cell culture and in vivo. The current study was undertaken to determine the effects of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on protein kinase C phosphotransferase activity in vitro. Various concentrations of DHA, EPA, and arachidonic acid (AA) were incubated with the catalytic domain of protein kinase C beta from rat brain. Protein kinase C activity was measured by quantifying incorporation of (32)P-PO(4) into a synthetic peptide substrate. Both DHA and EPA, as well as the combination of DHA and EPA, inhibited PKC activity at concentrations as low as 10 micromol l(-1). In contrast, arachidonic acid had no effect on PKC activity. Thus, PKC represents a potential site of action of omega-3 fatty acids in their effects on the treatment of bipolar disorder.
Mol Psychiatry 2001 Mar
PMID:Inhibitory effects of omega-3 fatty acids on protein kinase C activity in vitro. 1131 32

In an attempt to identify susceptibility loci for bipolar affective disorder, we are currently conducting a systematic genome screen with highly polymorphic microsatellite markers at an average marker spacing of 10 cM in a series of 75 families, comprising 66 families from Germany, eight families from Israel, and one family from Italy. The families were ascertained through index cases with bipolar affective disorder. The distribution of diagnoses is as follows: 126 individuals with bipolar I disorder, 40 with bipolar II disorder, 14 with schizoaffective disorder of the bipolar type, 40 individuals with recurrent unipolar depression, 51 with a minor psychiatric diagnosis, and two individuals with a diagnosis of schizophrenia. One hundred and seventy-one individuals are unaffected. Here, we present results from chromosome 10. Linkage analyses using a total of 33 microsatellite markers with parametric and non-parametric methods provided evidence for linkage at chromosomal region 10q25--q26. The highest two-point LOD score (2.86, theta = 0.05) was obtained for D10S217 using a dominant genetic model and a broad definition of affection status. The GENEHUNTER program localized the putative susceptibility locus within a ca 15-cM interval between markers D10S1483 and D10S217 with a maximum NPL(all) score of 3.12 (P = 0.0013). Positive linkage findings that have been reported by two independent studies further support the hypothesis of a susceptibility gene for bipolar affective disorder on 10q25-q26.
Mol Psychiatry 2001 May
PMID:A possible susceptibility locus for bipolar affective disorder in chromosomal region 10q25--q26. 1132 7

Recently, we have found an association between bipolar disorder patients who are excellent responders to lithium prophylaxis and a polymorphic marker located in the first intron of the phospholipase C-gamma1 gene (PLC-gamma1) [Turecki et al., 1998: Mol Psychiatry 3:534-538]. As this variant is not known to be functional, we searched for other markers within the coding region, using single-strand conformational polymorphism (SSCP) analysis. We have identified three polymorphic sites localized in three different exons of the PLC-gamma1 gene (exons 9, 26, 31). Variation studies of these potentially functional sites in a group of 133 bipolar patients with an excellent response to lithium prophylaxis and a comparison group of 99 healthy controls showed no difference in genotype distributions for exon 9 (chi-square = 1.41, df = 2, P = 0.49), exon 26 (chi-square = 2.26, df = 2, P = 0.13), or exon 31 (chi-square = 1.41, df = 2, P = 0.49). Similar results were observed for allele distributions. These results suggest that our previous findings were not the result of linkage disequilibrium with these variants.
 ...
PMID:Identification of three polymorphisms in the translated region of PLC-gamma1 and their investigation in lithium responsive bipolar disorder. 1135 54

Genes involved in the regulation of synaptic vesicle function are potential candidates for the development of psychiatric disorders. In addition to experimental and theoretical considerations, a number of genes involved in synaptic vesicle function map to regions of the genome that have been linked to bipolar disorder (BPD) and schizophrenia (SZ). One is synaptojanin 1 (SYNJ1) which maps to 21q22.2, a chromosomal region that has been linked to BPD in a subset of families in several studies. Synaptojanin 1 is an inositol 5-phosphatase that has an important role in synaptic vesicle endocytosis. Mutation screening of 32 exons, intron--exon junctions, and 839 bases of 5'-flanking DNA resulted in the identification of 11 mutations of which four were very common and seven were very rare. Of the 11 mutations identified, several may have functional significance including two coding variants, two that may affect the binding of a transcription factor, and two that involve known splicing regulatory domains. Five bipolar patients out of 149 analyzed were found who have one of the four rare variants that were most likely to have functional significance compared with 0/148 controls. The allele frequencies for three of the four common variants were very similar in bipolar patients and controls. A slight difference in allele frequency was found for an interesting mutation we detected in intron 12 in which two non-adjacent thymidine residues are deleted in a poly-AT tract located near the exon 12 splice donor site (chi(2) = 2.45, P = 0.12, 2-tailed). Although we failed to unequivocally identify a specific SYNJ1 allele that could be responsible for putative chromosome 21q22-linked BPD, several interesting variants were found to be increased in bipolar subjects and should be further investigated.
Mol Psychiatry 2001 Jul
PMID:Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder. 1144 22

Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. In this present study, we undertook a 10 cM genome screen using 400 microsatellite markers in a large multigenerational bipolar pedigree consisting of 40 individuals, including six affecteds. We found strongest evidence for linkage to chromosome 13q14. A maximum NPL score of 4.09 (P = 0.008) was obtained between markers D13S1272 and D13S153 using GENEHUNTER. A maximum two-point LOD score of 2.91 (theta = 0.0) was found for marker D13S153 and a maximum three-point LOD score of 3.0 was obtained between markers D13S291 and D13S153 under a recessive model with 90% maximum age-specific penetrance and including bipolar I and unipolar individuals as affected. Several other markers in the region, D13S175, D13S218, D13S263, and D13S156 had two-point LOD scores greater than 1.5. These results meet the criteria for evidence of suggestive linkage. Haplotype analysis enabled us to narrow the likely disease region to a 6 cM region between markers D13S1272 and D13S1319, which contains the serotonin 2A receptor candidate gene. Two single nucleotide polymorphisms were identified in this gene but we did not detect any significant differences in allele frequency in a case-control sample. The region on chromosome 13q14-32 has previously been implicated in other bipolar and schizophrenia cohorts. Our results provide further support for the existence of a susceptibility locus on chromosome 13q14.
Mol Psychiatry 2001 Jul
PMID:A genome screen of a large bipolar affective disorder pedigree supports evidence for a susceptibility locus on chromosome 13q. 1144 23

A number of studies have strongly suggested a susceptibility locus for bipolar affective disorder on chromosome 12q24. The present study investigates for a shared chromosomal segment among distantly related patients with bipolar affective disorder from the Faroe Islands, using 17 microsatellite markers covering 24 cM in the previously suggested region on chromosome 12q24. D12S342 showed possible allelic association to bipolar affective disorder (P-value using CLUMP below 0.01). Increased sharing among cases of two-marker haplotypes were suggested at D12S1614--D12S342 (P-values using CLUMP below 0.01), and D12S2075--D12S1675 (P-values using CLUMP around 0.001). The region of most interest is around 6 cM and bounded by markers D12S1614 and D12S1675 as suggested by the interesting two-marker haplotypes. This area contains the minimum interesting region between D12S342 and D12S1658 suggested by the previously reported haplotypes in the two Danish families with bipolar affective disorder.
Mol Psychiatry 2001 Jul
PMID:Further evidence for a bipolar risk gene on chromosome 12q24 suggested by investigation of haplotype sharing and allelic association in patients from the Faroe Islands. 1144 32

A method, model, and "operational equations" are described to quantify in vivo turnover rates and half-lives of fatty acids within brain phospholipids, as well as rates of incorporation of these fatty acids into brain from plasma. In awake rats, recycling of fatty acids within brain phospholipids, due to deesterification and reesterification, is very rapid, with half-lives in some cases of minutes to hours. Plasma fatty acids make only a small contribution (2-4%) to the net quantity of fatty acids that are reesterified. This explains why many weeks are necessary to recover normal brain n-3 polyunsaturated fatty acid concentrations following their prolonged dietary deprivation. Changes in recycling of specific fatty acids in response to centrally acting drugs can help to identify enzyme targets for drug action. For example, recycling of arachidonate is specifically reduced by 80% in rats treated chronically with lithium, a drug effective against bipolar disorder; the effect reflects downregulation of gene expression of an arachidonate-specific phospholipase A2. When combined with neuroimaging (quantitative autoradiography in rodents or positron-emission tomography [PET] in macaques or humans), intravenously injected radiolabeled fatty acids can be used to localize and quantify brain PLA2-mediated signal transduction, and to examine neuroplastic remodeling of brain lipid membranes.
J Mol Neurosci
PMID:In vivo fatty acid incorporation into brain phosholipids in relation to plasma availability, signal transduction and membrane remodeling. 1147 80


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