EGR genes as targets for the diagnosis and treatment of schizophrenia
First Claim
1. A method for the diagnosis of schizophrenia or schizophrenia susceptibility comprising:
- (i) providing a sample obtained from a subject to be tested for schizophrenia or schizophrenia susceptibility; and
(ii) detecting a polymorphic variant of a polymorphism in a coding or noncoding portion of a gene encoding an EGR molecule or encoding an EGR interacting molecule, or detecting a polymorphic variant of a polymorphism in a genomic region linked to such a gene, in the sample.
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Abstract
The present invention provides targets, methods, and reagents for the diagnosis and treatment of schizophrenia and related conditions. The invention provides methods for the diagnosis of schizophrenia and susceptibility to schizophrenia by detection of polymorphisms, mutations, variations, alterations in expression, etc., in genes encoding an EGR molecule or an EGR interacting molecule, or polymorphisms linked to such genes. The invention provides oligonucleotides, arrays, and antibodies for detection of polymorphisms and variants. The invention provides transgenic mice having alterations in such genes. The invention also provides methods of treating schizophrenia by administering compounds that target these genes. The invention further provides screening methods for identifying such compounds and compounds obtained by perfoming the screens.
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Citations
95 Claims
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1. A method for the diagnosis of schizophrenia or schizophrenia susceptibility comprising:
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(i) providing a sample obtained from a subject to be tested for schizophrenia or schizophrenia susceptibility; and
(ii) detecting a polymorphic variant of a polymorphism in a coding or noncoding portion of a gene encoding an EGR molecule or encoding an EGR interacting molecule, or detecting a polymorphic variant of a polymorphism in a genomic region linked to such a gene, in the sample. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 42, 66)
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18. A method for the diagnosis of schizophrenia or schizophrenia susceptibility comprising:
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(i) providing a sample obtained from a subject to be tested for schizophrenia or schizophrenia susceptibility; and
(ii) detecting an alteration or variation in expression or activity of an EGR molecule or an EGR interacting molecule, in the sample, relative to the expression or activity of the EGR molecule or EGR interacting molecule that would be expected in a sample obtained from a normal subject. - View Dependent Claims (19, 20, 21)
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22. A method for the diagnosis of schizophrenia or schizophrenia susceptibility comprising:
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(i) providing a sample obtained from a subject to be tested for schizophrenia or schizophrenia susceptibility; and
(ii) detecting an alteration or variation in an EGR molecule or EGR interacting molecule in the sample. - View Dependent Claims (23, 24, 25, 26)
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27. A method for treating schizophrenia or susceptibility to schizophrenia comprising:
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providing a subject at risk of or suffering from schizophrenia; and
administering a compound that modulates activity or abundance of an EGR molecule or EGR interacting molecule to the subject. - View Dependent Claims (28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41)
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43. A method of identifying a polymorphism useful in diagnosis of schizophrenia or susceptibility to schizophrenia comprising steps of:
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identifying one or more polymorphisms in or linked to a gene encoding an EGR molecule or EGR interacting molecule;
providing a set of samples including samples obtained from subjects affected with schizophrenia;
testing the samples for linkage or association of one or more variants of the polymorphism with schizophrenia; and
identifying the polymorphism as useful in diagnosis of schizophrenia if linkage or association exists between one or more variants of the polymorphism and schizophrenia susceptibility.
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44. A method of identifying a mutation that contributes to or causes schizophrenia or susceptibility to schizophrenia comprising steps of:
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identifying a polymorphism in or linked to a gene encoding an EGR molecule or EGR interacting molecule;
determining that a polymorphic variant of the polymorphism is linked to or associated with susceptibilty to schizophrenia;
sequencing the gene and optionally regulatory regions of the gene in a sample obtained from one or more subjects suffering from schizophrenia;
comparing the sequence obtained with a normal or wild type sequence of the same gene;
identifying the polymorphic variant as representing a mutation that causes or contributes to schizophrenia if the sequence obtained in the sequencing step differs from the normal or wild type sequence.
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45. A method for identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:
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providing a biological system comprising an EGR molecule and an EGR reporter;
contacting the biological system with a compound;
comparing the transcriptional response of the reporter in the presence of the compound with the response or expected response in the absence of the compound; and
identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the transcriptional response in the presence of the compound is different from the transcriptional response that occurs or would be expected in the absence of the compound. - View Dependent Claims (46, 47, 52, 63, 64, 65)
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48. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:
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providing a biological system comprising an EGR molecule and an endogenous EGR modulator;
contacting the biological system with the compound;
comparing extent or rate of binding of the EGR molecule and the endogenous EGR modulator in the presence of the compound with the extent or rate of binding that occurs or would be expected to occur in the absence of the compound; and
identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the extent or rate of binding of the EGR molecule and the endogenous EGR inhibitor in the presence of the compound is different from the extent or rate of binding that occurs or would be expected in the absence of the compound. - View Dependent Claims (49, 50)
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51. A method for identifying a candidate compound for treatment of schizophrenia or schizophrenia susceptibility comprising steps of:
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providing a molecular structure of an EGR molecule;
identifying a structure that is expected to bind to the EGR molecule or to prevent binding of the EGR molecule to an EGR interacting molecule; and
selecting a compound having such a structure as a candidate compound for treatment of schizophrenia or schizophrenia susceptibility.
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53. A method of identifying a compound for treatment of schizophrenia comprising steps of:
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providing a subject or subjects;
administering a candidate compound to the subject or subjects, wherein the candidate compound modulates activity or abundance of an EGR molecule or EGR interacting molecule;
comparing severity or incidence of the phenotype in the subject or subjects to severity or incidence of the phenotype to that existing or expected to exist in a subject or subjects to which the candidate compound is not administered; and
identifying the candidate compound as a compound for the treatment of schizophrenia or schizophrenia susceptibility if severity or incidence of the phenotype in the subject or subjects is less than that existing or expected to exist in a subject or subjects to which the compound is not administered.
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54. A method of identifying a compound for treatment of schizophrenia comprising steps of:
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providing a subject or subjects at risk of or exhibiting one or more phenotypes suggestive of schizophrenia, wherein the subject or subjects have an alteration in at least one EGR molecule or EGR interacting molecule or in a gene encoding such a molecule;
administering a candidate compound to the subject or subjects;
comparing severity or incidence of the phenotype in the subject or subjects to severity or incidence of the phenotype to that existing or expected to exist in a subject or subjects to which the candidate compound is not administered; and
identifying the candidate compound as a compound for the treatment of schizophrenia or schizophrenia susceptibility if severity or incidence of the phenotype in the subject or subjects is less than that existing or expected to exist in a subject or subjects to which the compound is not administered. - View Dependent Claims (55, 56, 57, 58, 59, 60, 61, 62)
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- 67. An oligonucleotide designed to specifically detect or amplify a naturally occurring polymorphic variant of a polymorphism in a coding or noncoding portion of a gene encoding an EGR molecule or EGR interacting molecule, or a polymorphic variant of a polymorphism in a genomic region linked to such a gene, wherein the gene or a portion thereof is coincident with a schizophrenia susceptibility locus.
- 70. An oligonucleotide designed to specifically detect or amplify a naturally occurring nucleic acid region comprising a polymorphic site in a coding or noncoding portion of a gene encoding an EGR molecule or EGR interacting molecule, or a polymorphic variant of a polymorphism in a genomic region linked to such a gene, wherein the gene or a portion thereof is coincident with a schizophrenia susceptibility locus.
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79. A primer that terminates at the nucleotide position immediately adjacent to a naturally occurring polymorphic site on the 3′
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direction from this site, wherein the polymorphic site is the site of a polymorphism in a coding or noncoding portion of a gene encoding an EGR molecule or EGR interacting molecule or is the site of a polymorphism in a genomic region linked to such a gene. - View Dependent Claims (80, 81, 82, 83, 84, 85)
- side and extends at least 8 and less than 100 nucleotides in the 5′
- 86. An siRNA or shRNA molecule targeted to a transcript encoding an EGR molecule or EGR interacting molecule.
- 92. An antibody that specifically binds to a variant of an EGR molecule or EGR interacting molecule, wherein the calcineurin subunit or calcineurin interacting molecule is encoded by a gene comprising a polymorphic variant, wherein existence of the polymorphic variant in a subject is indicative of susceptibility to or presence of schizophrenia.
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95. A database comprising a list of polymorphic sequences stored on a computer-readable medium, wherein the polymorphic sequences occur in a coding or noncoding portion of a gene encoding an EGR molecule or EGR interacting molecule, or in a genomic region linked to such a gene, and wherein the list is largely or entirely limited to polymorphisms have been identified as useful in performing genetic diagnosis of schizophrenia or susceptibility to schizophrenia, or for performing genetic studies of schizophrenia or susceptibility to schizophrenia.
Specification