Methods and compositions for the diagnosis and treatment of neuropsychiatric disorders

Abstract

The present invention relates to the mammalian fsh22 gene, a novel gene associated with bipolar affective disorder (BAD) in humans. The invention encompasses fsh22 nucleic acids, recombinant DNA molecules, cloned genes or degenerate variants thereof, fsh22 gene products and antibodies directed against such gene products, cloning vectors containing mammalian fsh22 gene molecules, and hosts that have been genetically engineered to express such molecules. The invention further relates to methods for the identification of compounds that modulate the expression of fsh22 and to using such compounds as therapeutic agents in the treatment of fsh22 disorders and neuropsychiatric disorders. The invention also relates to methods for the diagnostic evaluation, genetic testing and prognosis of fsh22 disorders and neuropsychiatric disorders including schizophrenia, attention deficit disorder, a schizoaffective disorder, a bipolar affective disorder or a unipolar affective disorder, and to methods and compositions for the treatment these disorders.

What is claimed is:  
     
         1 . An isolated nucleic acid molecule comprising: 
 a. a nucleic acid molecule encoding a polypeptide comprising the amino acid sequence shown in FIG. 1 (SEQ. ID NO. 2); or    b. a nucleic acid molecule encoding a polypeptide comprising the amino acid sequence encoded by the nucleic acid insert of the clone contained in ATCC accession No. 98350.    
     
     
         2 . The isolated nucleic acid molecule of  claim 1  wherein the nucleic acid molecule contains the nucleotide sequence shown in FIG. 1 (SEQ. ID NO. 1).  
     
     
         3 . An isolated nucleic acid molecule which hybridizes to the complement of the nucleic acid molecule of  claim 1  and encodes a polypeptide involved in a neuropsychiatric disorder.  
     
     
         4 . The isolated nucleic acid molecule of  claim 3  wherein the neuropsychiatric disorder is schizophrenia, attention deficit disorder, a schizoaffective disorder, a bipolar affective disorder or a unipolar affective disorder.  
     
     
         5 . The isolated nucleic acid molecule of  claim 4  wherein the bipolar affective disorder is severe bipolar affective (mood) disorder, bipolar affective (mood) disorder with hypomania and major depression, or schizoaffective disorder manic type.  
     
     
         6 . The isolated nucleic acid molecule of  claim 4  wherein the unipolar affective disorder is unipolar major depressive disorder.  
     
     
         7 . An isolated nucleic acid molecule which hybridizes under stringent conditions to the complement of the nucleic acid molecule of  claim 1 .  
     
     
         8 . The isolated nucleic acid molecule of  claim 3  or  7  wherein the nucleic acid molecule encodes a naturally occurring polypeptide.  
     
     
         9 . A nucleotide vector containing the nucleotide sequence of  claim 1 ,  3  or  7 .  
     
     
         10 . An expression vector containing the nucleotide sequence of  claim 1 ,  3  or  7  in operative association with a nucleotide regulatory sequence that controls expression of the nucleotide sequence in a host cell.  
     
     
         11 . The expression vector of  claim 10 , wherein said regulatory element is selected from the group consisting of the cytomegalovirus hCMV immediate early gene, the early or late promoters of SV40 adenovirus, the lac system, the trp system, the TAC system, the TRC system, the major operator and promoter regions of phage A, the control regions of fd coat protein, the promoter for 3-phosphoglycerate kinase, the promoters of acid phosphatase, and the promoters of the yeast α-mating factors.  
     
     
         12 . A genetically engineered host cell that contains the nucleotide sequence of  claim 1 ,  3  or  7 .  
     
     
         13 . A genetically engineered host cell that contains the nucleotide sequence of  claim 1 ,  3  or  7  in operative association with a nucleotide regulatory sequence that controls expression of the nucleotide sequence in the host cell.  
     
     
         14 . An isolated gene product comprising: 
 a. the amino acid sequence shown in FIG. 1 (SEQ. ID NO. 2); or    b. the amino acid sequence encoded by the nucleic acid insert of the clone contained in ATCC accession No. 98350.    
     
     
         15 . An isolated gene product encoded by the nucleic acid molecule of  claim 3  or  7 .  
     
     
         16 . An antibody that immunospecifically binds the gene product of  claim 14 .  
     
     
         17 . An antibody that immunospecifically binds the gene product of  claim 15 .  
     
     
         18 . A method for diagnosing a neuropsychiatric disorder in a mammal, comprising: measuring fsh22 gene expression in a patient sample.  
     
     
         19 . The method of  claim 18  wherein the neuropsychiatric disorder is schizophrenia, attention deficit disorder, a schizoaffective disorder, a bipolar affective disorder or a unipolar disorder.  
     
     
         20 . The method of  claim 19  wherein the bipolar affective disorder is severe bipolar affective (mood) disorder, bipolar affective (mood) disorder with hypomania and major depression, or schizoaffective disorder manic type.  
     
     
         21 . The method of  claim 19  wherein the unipolar affective disorder is unipolar major depressive disorder.  
     
     
         22 . The method of  claim 18  in which expression is measured by detecting fsh22 mRNA transcripts.  
     
     
         23 . The method of  claim 18  in which expression is measured by detecting fsh22 gene product.  
     
     
         24 . A method for diagnosing a fsh22 disorder in a mammal, comprising: measuring fsh22 gene expression in a patient sample.  
     
     
         25 . The method of  claim 24  in which expression is measured by detecting fsh22 mRNA transcripts.  
     
     
         26 . The method of  claim 24  in which expression is measured by detecting fsh22 gene product.  
     
     
         27 . A method for diagnosing a neuropsychiatric disorder in a mammal, comprising: detecting a fsh22 gene mutation contained in the genome of the mammal.  
     
     
         28 . The method of  claim 27  wherein the neuropsychiatric disorder is schizophrenia, attention deficit disorder, a schizoaffective disorder, a bipolar affective disorder or a unipolar disorder.  
     
     
         29 . The method of  claim 28  wherein the bipolar affective disorder is severe bipolar affective (mood) disorder, bipolar affective (mood) disorder with hypomania and major depression, or schizoaffective disorder manic type.  
     
     
         30 . The method of  claim 28  wherein the unipolar affective disorder is unipolar major depressive disorder.  
     
     
         31 . A method for diagnosing a fsh22 disorder in a mammal, comprising: detecting a fsh22 gene mutation contained in the genome of the mammal.  
     
     
         32 . A method for identifying a compound capable of modulating a fsh22 activity, comprising: 
 a. contacting a compound to a cell that expresses a fsh22 gene;    b. measuring the level of fsh22 gene expression in the cell; and    c. comparing the level obtained in (b) to fsh22 gene expression level obtained in the absence of the compound;    such that if the level obtained in (b) differs from that obtained in the absence of the compound, a compound capable of modulating a fsh22 activity has been identified.    
     
     
         33 . The method of  claim 32  wherein the compound increases the level of fsh22 gene expression.  
     
     
         34 . The method of  claim 32  wherein the compound decreases the level of fsh22 gene expression.  
     
     
         35 . The method of  claim 32  in which expression of the fsh22 gene is detected by measuring fsh22 mRNA transcripts.  
     
     
         36 . The method of  claim 32  in which expression of the fsh22 gene is detected by measuring fsh22 gene product.  
     
     
         37 . The method of  claim 32  wherein the compound is a small organic molecule.  
     
     
         38 . A method for identifying a compound capable of treating a neuropsychiatric disorder, comprising: 
 a. contacting a compound to a cell that expresses a fsh22 gene;    b. measuring the level of fsh22 gene expression in the cell; and    c. comparing the level obtained in (b) to fsh22 gene expression level obtained in the absence of the compound;    such that if the level obtained in (b) differs from that obtained in the absence of the compound, a compound capable of treating a neuropsychiatric disorder has been identified.    
     
     
         39 . The method of  claim 38  wherein the neuropsychiatric disorder is schizophrenia, attention deficit disorder, a schizoaffective disorder, a bipolar affective disorder or a unipolar disorder.  
     
     
         40 . The method of  claim 39  wherein the bipolar effective disorder is severe bipolar affective (mood) disorder, bipolar affective (mood) disorder with hypomania and major depression, or schizoaffective disorder manic type.  
     
     
         41 . The method of  claim 39  wherein the unipolar affective disorder is unipolar major depressive disorder.  
     
     
         42 . The method of  claim 38  wherein the compound increases the level of fsh22 gene expression.  
     
     
         43 . The method of  claim 38  wherein the compound decreases the level of fsh22 gene expression.  
     
     
         44 . The method of  claim 38  in which expression of the fsh22 gene is detected by measuring fsh22 mRNA transcripts.  
     
     
         45 . The method of  claim 38  in which expression of the fsh22 gene is detected by measuring fsh22 gene product.  
     
     
         46 . The method of  claim 38  in which the compound is a small organic molecule.  
     
     
         47 . A method for treating a neuropsychiatric disorder in a mammal comprising administering to the mammal a compound to the mammal that modulates the synthesis, expression or activity of a mammalian fsh22 gene or fsh22 gene product so that symptoms of the disorder are ameliorated.  
     
     
         48 . The method of  claim 47  wherein the neuropsychiatric disorder is schizophrenia, attention deficit disorder, a schizoaffective disorder, a bipolar affective disorder or a unipolar disorder.  
     
     
         49 . The method of  claim 48  wherein the bipolar affective disorder is severe bipolar affective (mood) disorder, bipolar affective (mood) disorder with hypomania and major depression, or schizoaffective disorder manic type.  
     
     
         50 . The method of  claim 47  wherein the unipolar affective disorder is unipolar major depressive disorder.  
     
     
         51 . The method of  claim 47  wherein the compound increases the synthesis, expression or activity of a mammalian fsh22 gene or fsh22 gene product.  
     
     
         52 . The method of  claim 51  wherein the compound comprises the nucleic acid molecule of  claim 1 ,  3  or  7 .  
     
     
         53 . The method of  claim 51  wherein the compound is a small organic molecule.  
     
     
         54 . The method of  claim 47  wherein the compound decreases the synthesis, expression or activity of a mammalian fsh22 gene or fsh22 gene product.  
     
     
         55 . The method of  claim 54  wherein the compound provides an antisense or ribozyme molecule that blocks translation of fsh22 mRNAs.  
     
     
         56 . The method of  claim 54  wherein the compound provides a nucleic acid molecule that is complementary to a fsh22 gene and blocks fsh22 transcription via triple helix formation.  
     
     
         57 . The method of  claim 54  wherein the compound is a small organic molecule.  
     
     
         58 . A method for treating a fsh22 disorder in a mammal comprising administering to the mammal a compound to the mammal that modulates the synthesis, expression or activity of a mammalian fsh22 gene or fsh22 gene product so that symptoms of the disorder are ameliorated.  
     
     
         59 . The method of  claim 58  wherein the compound increases the synthesis, expression or activity of a mammalian fsh22 gene or fsh22 gene product.  
     
     
         60 . The method of  claim 59  wherein the compound comprises the nucleic acid molecule of  claim 1 ,  3  or  7 .  
     
     
         61 . The method of  claim 59  wherein the compound is a small organic molecule.  
     
     
         62 . The method of  claim 58  wherein the compound decreases the synthesis, expression or activity of a mammalian fsh22 gene or fsh22 gene product.  
     
     
         63 . The method of  claim 62  wherein the compound provides an antisense or ribozyme molecule that blocks translation of fsh22 mRNAs.  
     
     
         64 . The method of  claim 62  wherein the compound provides a nucleic acid molecule that is complementary to a fsh22 gene and blocks fsh22 transcription via triple helix formation.  
     
     
         65 . The method of  claim 62  wherein the compound is a small organic molecule.  
     
     
         66 . A method of treating a neuropsychiatric disorder resulting from a mutation in a fsh22 gene, in a mammal, comprising supplying the mammal with a nucleic acid molecule that encodes an unimpaired fsh22 gene product such that an unimpaired fsh22 gene product is expressed and symptoms of the disorder are ameliorated.  
     
     
         67 . The method of  claim 66  wherein the neuropsychiatric disorder is schizophrenia, attention deficit disorder, a schizoaffective disorder, a bipolar affective disorder or a unipolar disorder.  
     
     
         68 . The method of  claim 67  wherein the bipolar affective disorder is severe bipolar affective (mood) disorder, bipolar affective (mood) disorder with hypomania and major depression, or schizoaffective disorder manic type.  
     
     
         69 . The method of  claim 67  wherein the unipolar affective disorder is unipolar major depressive disorder.  
     
     
         70 . The method of  claim 66  in which a nucleic acid molecule encoding the unimpaired fsh22 protein, contained in a pharmaceutically acceptable carrier, is administered to the mammal.  
     
     
         71 . The method of  claim 70  in which the carrier is a DNA vector, a viral vector, a liposome or lipofectin.  
     
     
         72 . The method of  claim 66  in which the nucleic acid encoding an unimpaired fsh22 protein is introduced into the brain of the mammal.  
     
     
         73 . A method of treating a fsh22 disorder resulting from a mutation in a fsh22 gene in a mammal, comprising supplying the mammal with a nucleic acid molecule that encodes an unimpaired fsh22 gene product such that an unimpaired fsh22 gene product is expressed and symptoms of the disorder are ameliorated.  
     
     
         74 . The method of  claim 73  in which a nucleic acid molecule encoding an unimpaired fsh22 protein, contained in a pharmaceutically acceptable carrier, is administered to the mammal.  
     
     
         75 . The method of  claim 74  in which the carrier is a DNA vector, a viral vector, a liposome or lipofectin.  
     
     
         76 . A method of treating a neuropsychiatric disorder resulting from a mutation in a fsh22 gene in a mammal, comprising supplying the mammal with a cell comprising a nucleic acid molecule that encodes an unimpaired fsh22 gene product such that the cell expresses unimpaired fsh22 gene product and symptoms of the neuropsychiatric disorder are ameliorated.  
     
     
         77 . The method of  claim 76  wherein the neuropsychiatric disorder is schizophrenia, attention deficit disorder, a schizoaffective disorder, a bipolar affective disorder or a unipolar disorder.  
     
     
         78 . The method of  claim 77  wherein the bipolar affective disorder is severe bipolar affective (mood) disorder, bipolar affective (mood) disorder with hypomania and major depression, or schizoaffective disorder manic type.  
     
     
         79 . The method of  claim 77  wherein the unipolar affective disorder is unipolar major depressive disorder.  
     
     
         80 . The method of  claim 76  in which the cell is engineered ex vivo to express an unimpaired fsh22 protein.  
     
     
         81 . The method of  claim 76  in which the cell is contained in a carrier.  
     
     
         82 . The method of  claim 76  in which a nucleic acid molecule encoding an unimpaired fsh22 protein, contained in a pharmaceutically acceptable carrier, is administered to the mammal.  
     
     
         83 . The method of  claim 82  in which the carrier is a DNA vector, a viral vector, a liposome or lipofectin.  
     
     
         84 . A method of treating a fsh22 disorder resulting from a mutation in a fsh22 gene in a mammal, comprising supplying the mammal with a cell comprising a nucleic acid molecule that encodes an unimpaired fsh22 gene product such that the cell expresses unimpaired fsh22 gene product and symptoms of the disorder are ameliorated.  
     
     
         85 . The method of  claim 84  in which the cell is engineered ex vivo to express an unimpaired fsh22 protein.  
     
     
         86 . The method of  claim 84  in which the cell is contained in a carrier.  
     
     
         87 . The method of  claim 84  in which a nucleic acid molecule encoding an unimpaired fsh22 protein, contained in a pharmaceutically acceptable carrier, is administered to the mammal.  
     
     
         88 . The method of  claim 84  in which the carrier is a DNA vector, a viral vector, a liposome or lipofectin.  
     
     
         89 . A method of mapping a human chromosome 18q region spanning DS18S1121 and 18SS30 chromosomal markers comprising identifying, aligning and detecting fsh22 polymorphisms within the 18q region.