Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two intronic polymorphisms of the human alpha subunit of the olfactory G-protein (G(olf)) are described. They were detected with single-stranded conformational polymorphism (SSCP) methods and confirmed by sequencing both strands. These single base pair (bp) substitutions occur in introns 3 (an A/G at 35 bp 3' from the exon 3/intron 3 5' splice site) and 10 (an T/G at 7 bp 5' from the 3' splice site). Both polymorphisms are relatively common, with minor allele frequencies of 31% (intron 3) and 16% (intron 10). The intron 3 variant shows no linkage disequilibrium with an intron 5 (CA)n microsatellite located approximately 50 kb 3' from the intron 3 variant, among a small group of German individuals with schizophrenia. The intron 3 variant is interesting because it may create an 'in-frame' cryptic splice site which, if activated, would add 12 residues to exon 3. The intron 10 variant is interesting because a purine is substituted for a pyrimidine in the 'polypyrimidine' tract of the 3' splice site, a single base substitution of the type which has been associated with aberrant splicing in the androgen receptor gene.
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PMID:Human G(olf) gene polymorphisms and vulnerability to bipolar disorder. 1069 28

Hemizygous cryptic deletions of the q11 band of human chromosome 22 have been associated with a number of psychiatric and behavioural phenotypes, including schizophrenia. Here we report the isolation and characterization of PRODH, a human homologue of Drosophila melanogaster sluggish-A (slgA), which encodes proline dehydrogenase responsible for the behavioural phenotype of the slgA mutant. PRODH is localized at chromosome 22q11 in a region deleted in some psychiatric patients. We also isolated the mouse homologue of slgA (Prodh), identified a mutation in this gene in the Pro/Re hyperprolinaemic mouse strain and found that these mice have a deficit in sensorimotor gating accompanied by regional neurochemical alterations in the brain. Sensorimotor gating is a neural filtering process that allows attention to be focused on a given stimulus, and is affected in patients with neuropsychiatric disorders. Furthermore, several lines of evidence suggest that proline may serve as a modulator of synaptic transmission in the mammalian brain. Our observations, in conjunction with the chromosomal location of PRODH, suggest a potential involvement of this gene in the 22q11-associated psychiatric and behavioural phenotypes.
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PMID:The gene encoding proline dehydrogenase modulates sensorimotor gating in mice. 1019 98

Chromosome anomalies are responsible for a significant proportion of patients with mental retardation, and congenital anomalies. Development of new molecular cytogenetic techniques has provided a powerful tool for detection of patients with subtle chromosome abnormalities. Particularly, investigation of the gene-rich subtelomeric regions has generated interest regarding the implications and prevalence of cryptic chromosomal rearrangements. Here we describe an adult with a submicroscopic deletion of 18pter, detected by subtelomeric FISH probe. The patient is a 42-year-old man with a history of developmental delay, moderate mental retardation, and symptoms of paranoid schizophrenia since adolescence. His physical examination is remarkable for only a few dysmorphic findings typically seen in 18p- syndrome (round face, hypertelorism, down-slanted palpebral fissures, temporal narrowing, small hands and feet). He lacks significant short stature, skin changes, and associated anomalies involving internal organs. All known patients with deletions of the short arm of chromosome 18 have either loss of large parts of 18p or of the entire p-arm, or have complex chromosomal rearrangement involving other chromosomes. To our knowledge, this is the first description of a cryptic subtelomeric deletion of 18p and the first case of such a chromosomal anomaly in a patient with schizophrenia. Small subtelomeric chromosomal deletions would be missed by standard G-banded karyotyping. Therefore, FISH analysis using subtelomeric probes should be considered for diagnostic evaluation of patients with psychiatric symptoms and mental retardation in whom the karyotype is normal.
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PMID:Subtelomeric deletion of 18p in an adult with paranoid schizophrenia and mental retardation. 1470 8

Schizophrenia (SZ) is one of the most cryptic and costly mental disorders in terms of human suffering and societal expenditure (van Os and Kapur, 2009). Though strong evidence for functional, structural, and genetic abnormalities associated with this disease exists, there is yet no replicable finding which has proven accurate enough to be useful in clinical decision making (Fornito et al., 2009), and its diagnosis relies primarily upon symptom assessment (Williams et al., 2010a). It is likely in part that the lack of consistent neuroimaging findings is because most models favor only one data type or do not combine data from different imaging modalities effectively, thus missing potentially important differences which are only partially detected by each modality (Calhoun et al., 2006a). It is becoming increasingly clear that multimodal fusion, a technique which takes advantage of the fact that each modality provides a limited view of the brain/gene and may uncover hidden relationships, is an important tool to help unravel the black box of schizophrenia. In this review paper, we survey a number of multimodal fusion applications which enable us to study the schizophrenia macro-connectome, including brain functional, structural, and genetic aspects and may help us understand the disorder in a more comprehensive and integrated manner. We also provide a table that characterizes these applications by the methods used and compare these methods in detail, especially for multivariate models, which may serve as a valuable reference that helps readers select an appropriate method based on a given research question.
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PMID:A selective review of multimodal fusion methods in schizophrenia. 2237 14

Unique mental abilities have been crucial for evolutionary success of Homo sapiens and for the development of his complex social organization. However, these abilities have also become a target for mental disorders which often result in a reduced fitness and in conflicts between the individual and the conventions of society. To account for this evolutionary maladaptation, we advance a new concept: that of "mis-exaptation", derived from SJ Gould and E Vrba's concept of exaptation. Mis-exaptation is a characteristic which, although it may confer positive effects in one field of activity, may reach an inappropriate degree of specialisation to have deleterious effects in that or in another field thereby leading to a decrease in fitness of the individual. This paper considers "inner speech" as an exaptation. Although inner speech is usually a positive aid to learning and reasoning, it may also favour the emergence of mental disturbances, such as the auditory hallucinations which are characteristic of schizophrenia. There is, nevertheless, a possible evolutionary value in mis-exaptational inner speech; two traits associated with the mis-exapted state would be altruistic behaviour and heightened creativity, the latter being over-expressed in relatives of schizophrenic patients. A possible solution for the evolutionary-genetic paradox posed by altruism and schizophrenia arising from mis-exaptation will be suggested in the light of a cryptic genetic repertoire. A selection of illustrative examples of each of these mental states is presented as they appear in the pages of the European literature. This article is part of a Special Issue entitled: Brain Integration.
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PMID:Possible genetic and epigenetic links between human inner speech, schizophrenia and altruism. 2248 63

Balanced chromosome abnormalities (BCAs) occur at a high frequency in healthy and diseased individuals, but cost-efficient strategies to identify BCAs and evaluate whether they contribute to a phenotype have not yet become widespread. Here we apply genome-wide mate-pair library sequencing to characterize structural variation in a patient with unclear neurodevelopmental disease (NDD) and complex de novo BCAs at the karyotype level. Nucleotide-level characterization of the clinically described BCA breakpoints revealed disruption of at least three NDD candidate genes (LINC00299, NUP205, PSMD14) that gave rise to abnormal mRNAs and could be assumed as disease-causing. However, unbiased genome-wide analysis of the sequencing data for cryptic structural variation was key to reveal an additional submicroscopic inversion that truncates the schizophrenia- and bipolar disorder-associated brain transcription factor ZNF804A as an equally likely NDD-driving gene. Deep sequencing of fluorescent-sorted wild-type and derivative chromosomes confirmed the clinically undetected BCA. Moreover, deep sequencing further validated a high accuracy of mate-pair library sequencing to detect structural variants larger than 10 kB, proposing that this approach is powerful for clinical-grade genome-wide structural variant detection. Our study supports previous evidence for a role of ZNF804A in NDD and highlights the need for a more comprehensive assessment of structural variation in karyotypically abnormal individuals and patients with neurocognitive disease to avoid diagnostic deception.
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PMID:Sequencing of a patient with balanced chromosome abnormalities and neurodevelopmental disease identifies disruption of multiple high risk loci by structural variation. 2462 50

We report locus-specific disintegration of megabase-scale chromosomal conformations in brain after neuronal ablation of Setdb1 (also known as Kmt1e; encodes a histone H3 lysine 9 methyltransferase), including a large topologically associated 1.2-Mb domain conserved in humans and mice that encompasses >70 genes at the clustered protocadherin locus (hereafter referred to as cPcdh). The cPcdh topologically associated domain (TADcPcdh) in neurons from mutant mice showed abnormal accumulation of the transcriptional regulator and three-dimensional (3D) genome organizer CTCF at cryptic binding sites, in conjunction with DNA cytosine hypomethylation, histone hyperacetylation and upregulated expression. Genes encoding stochastically expressed protocadherins were transcribed by increased numbers of cortical neurons, indicating relaxation of single-cell constraint. SETDB1-dependent loop formations bypassed 0.2-1 Mb of linear genome and radiated from the TADcPcdh fringes toward cis-regulatory sequences within the cPcdh locus, counterbalanced shorter-range facilitative promoter-enhancer contacts and carried loop-bound polymorphisms that were associated with genetic risk for schizophrenia. We show that the SETDB1 repressor complex, which involves multiple KRAB zinc finger proteins, shields neuronal genomes from excess CTCF binding and is critically required for structural maintenance of TADcPcdh.
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PMID:The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain. 2867 86