Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii. 1855 48

Nonsense mutations underlie about 10% of rare genetic disease cases. They introduce a premature termination codon (PTC) and prevent the formation of full-length protein. Pharmaceutical gentamicin, a mixture of several related aminoglycosides, is a frequently used antibiotic in humans that can induce PTC readthrough and suppress nonsense mutations at high concentrations. However, testing of gentamicin in clinical trials has shown that safe doses of this drug produce weak and variable readthrough activity that is insufficient for use as therapy. In this study we show that the major components of pharmaceutical gentamicin lack PTC readthrough activity but the minor component gentamicin B1 (B1) is a potent readthrough inducer. Molecular dynamics simulations reveal the importance of ring I of B1 in establishing a ribosome configuration that permits pairing of a near-cognate complex at a PTC. B1 induced readthrough at all three nonsense codons in cultured cancer cells with TP53 (tumor protein p53) mutations, in cells from patients with nonsense mutations in the TPP1 (tripeptidyl peptidase 1), DMD (dystrophin), SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), and COL7A1 (collagen type VII alpha 1 chain) genes, and in an in vivo tumor xenograft model. The B1 content of pharmaceutical gentamicin is highly variable and major gentamicins suppress the PTC readthrough activity of B1. Purified B1 provides a consistent and effective source of PTC readthrough activity to study the potential of nonsense suppression for treatment of rare genetic disorders.
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PMID:Gentamicin B1 is a minor gentamicin component with major nonsense mutation suppression activity. 3047 49