| Abstract | Many genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind to influenza, rubella, or poliovirus genes. Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease. |
| Abstract | Tissue-specific expression of the CALR gene in the brain gray matter in late-adolescence and early adulthood coincides with the expression of the psychoses phenotypes. Indeed, increased expression of the chaperone genes in the prefrontal cortex has been reported in patients affected by schizophrenia. We have previously reported cases of psychosis-associated mutations in the CALR gene promoter. One of those mutations at -48 was found to increase the expression of the gene in comparison with the wild type sequence. A recently identified mutation at -220 reverts the conserved block harboring nucleotide -220 to the ancestral type, and has an approximate prevalence of 0.7% in psychoses. In this study, we analyzed the functional implication of this mutation in the human neuroblastoma cell line BE(2)-C, and non-neural Human Embryonic Kidney 293 (HEK-293), and show that the -220A mutation results in a constitutive increase in the expression of the CALR gene (p<0.0003). We checked homology of the first 1000-bp CALR promoter sequence across species, and found that nucleotide -220C is the only human-unique nucleotide in that stretch. The -220A mutation, on the other hand, co-occurs with severe cognition deficit in humans, and is the rule across the species except humans. To our knowledge, the -220A mutation is the first reported instance of a cognition-deficit-associated mutation which reverses a human gene promoter to the primitive type. It may be speculated that, at least the basal transcription of the CALR gene, relating to the proximal promoter region, has been decreased during the process of evolution to humans. |
| Abstract | Development-dependent, tissue-specific expression of the CALReticulin (CALR) gene in the gray matter coincides with the expression of psychoses phenotypes. We have recently reported instances of mutations within the core promoter sequence of the gene in schizoaffective disorder. In view of the mounting evidence on the genetic overlap in the psychiatric spectrum, we investigated this gene in a spectrum of patients afflicted with schizophrenia, schizoaffective disorder and major affective disorder. We found that a unique mutation at nucleotide -220 from the transcription start site, located at a conserved genomic block in the promoter region of the gene, co-occurs with the spectrum of psychoses (p<0.005). This mutation reverts the human promoter sequence to the ancestral type observed in chimpanzee, mouse, and several other species, implying that the genomic block harboring nucleotide -220 may be involved in the evolution of human-specific higher-order functions of the brain (e.g. language, conceptual thinking, and judgment), that are ubiquitously impaired in psychoses. We propose that CALR is not only a promising candidate in the spectrum of psychoses, but also, a gene that may be important in the human-unique brain processes. |