Chromosomal markers and diagnostic tests for manic-depressive illness

Abstract

Methods and compositions are provided for determining a genotype associated with increased susceptibility to manic-depressive illness. The genotype is determined using markers for a region of chromosome 18 exhibiting linkage disequilibrium with manic-depressive illness. The invention also provides for a novel myo-inositol monophosphatase protein encoded for on chromosome 18.

What is claimed is:  
     
         1 . A method for determining a genotype associated with increased susceptibility to manic-depressive illness, comprising determining the genotype of an affected individual with at least one polymorphic marker localized within the chromosomal region defined by and including markers D18S843 and D18S869 and determining therefrom the genotype associated with increased susceptibility to manic-depressive disorder.  
     
     
         2 . The method of  claim 1 , wherein said polymorphic marker is amplified by primers which selectively hybridize, under stringent conditions, to the same nucleic acid sequences as primers of SEQ ID NO:1 and SEQ ID NO:2.  
     
     
         3 . The method of  claim 1 , wherein said polymorphic marker is amplified by the polymerase chain reaction.  
     
     
         4 . The method of  claim 1 , further comprising: 
 determining the genotype of a tested individual wherein the genotype is determined with at least one polymorphic marker localized within the chromosomal region defined by and including markers D18S843 and D18S869;    comparing the genotype of the tested individual to the genotype associated with increased susceptibility to manic-depressive illness; and    determining therefrom the increased or decreased risk of the tested individual developing manic-depressive illness.    
     
     
         5 . The method of  claim 4 , wherein said polymorphic marker is amplified by primers which selectively hybridize, under stringent conditions, to the same nucleic acid sequences as primers of SEQ ID NO:1 and SEQ ID NO:2.  
     
     
         6 . A nucleic acid composition, comprising oligonucleotide primers which selectively hybridize, under stringent conditions, to the same nucleic acid sequence as primers of SEQ ID NO:1 and SEQ ID NO:2.  
     
     
         7 . An isolated nucleic acid of less than 10 kB in length and comprising a polymorphic marker amplified by oligonucleotide primers of SEQ ID NO:1 and SEQ ID NO:2.  
     
     
         8 . A method for determining an increased susceptibility to manic-depressive illness in a tested individual, comprising determining the genotype of the tested individual with oligonucleotide primers which amplify the same polymorphic marker as primers of SEQ ID NO:1 and SEQ ID NO:2, wherein the presence of allele 2 of the polymorphic marker indicates an increased susceptibility to manic-depressive illness.  
     
     
         9 . An isolated nucleic acid encoding an IMP.18p myo-inositol monophosphatase, said protein defined as follows: 
 (i) having a calculated molecular weight of between about 22 to 34 kDa;    (ii) the protein's activity includes hydrolysis of myo-inositol 1-phosphate to generate inositol and inorganic phosphate; and    (iii) (a) specifically binding to an antibody raised against an IMP.18p myo-inositol monophosphatase protein, or immunogenic fragment thereof, consisting of SEQ ID NO:17; or 
 (b) having at least 60% amino acid sequence identity to an IMP.18p myo-inositol monophosphatase protein consisting of SEQ ID NO:17, as measured using a sequence comparison algorithm.  
   
     
     
         10 . The isolated nucleic acid of  claim 9 , wherein the calculated molecular weight of the encoded protein is about 28 to 29 kDa.  
     
     
         11 . The isolated nucleic acid of  claim 9 , wherein the encoded protein has at least 80% amino acid sequence identity to the IMP.18p myo-inositol monophosphatase protein of SEQ ID NO. 17, as measured using a sequence comparison algorithm.  
     
     
         12 . The isolated nucleic acid of  claim 9 , wherein the encoded protein has the sequence set forth in SEQ ID NO:17.  
     
     
         13 . An isolated nucleic acid which specifically hybridizes to SEQ ID NO:16 under stringent conditions.  
     
     
         14 . An isolated nucleic acid encoding an IMP.18p myo-inositol monophosphatase protein which specifically binds to an antibody directed against a protein having a sequence as set forth in SEQ ID NO:17.  
     
     
         15 . A polynucleotide or fragment thereof comprising a purified antisense nucleotide capable of hybridizing to and having a nucleic acid sequence complementary to at least a portion of an IMP.18p myo-inositol monophosphatase polynucleotide encoding an IMP.18p myo-inositol monophosphatase protein, said protein defined as follows: 
 (i) having a calculated molecular weight of between about 22 to 34 kDa;    (ii) the protein's activity includes hydrolysis of myo-inositol 1-phosphate to generate inositol and inorganic phosphate; and    (iii) (a) specifically binding to an antibody raised against an IMP.18p myo-inositol monophosphatase protein, or immunogenic fragment thereof, consisting of SEQ ID NO:17; or 
 (b) having at least 60% amino acid sequence identity to an IMP.18p myo-inositol monophosphatase protein consisting of SEQ ID NO:17, as measured using a sequence comparison algorithm.  
   
     
     
         16 . An expression vector comprising a nucleic acid encoding: 
 an IMP.18p myo-inositol monophosphatase protein, said protein defined as follows (i) having a calculated molecular weight of between about 22 to 34 kDa, 
 (ii) the protein's activity includes hydrolysis of myo-inositol l-phosphate to generate inositol and inorganic phosphate, and  
 (iii) (a) specifically binding to an antibody raised against an IMP.18p myo-inositol monophosphatase protein, or immunogenic fragment thereof, consisting of SEQ ID NO:17, or 
 (b) having at least 60% amino acid sequence identity to an IMP.18p myo-inositol monophosphatase protein consisting of SEQ ID NO:17, as measured using a sequence comparison algorithm; or,  
 
 an antisense nucleic acid sequence complementary to at least a portion of the IMP.18p myo-inositol monophosphatase polynucleotide.  
   
     
     
         17 . A cell comprising an exogenous nucleic acid sequence comprising a nucleic acid which encodes: 
 an IMP.18p myo-inositol monophosphatase protein, said protein defined as follows (i) having a calculated molecular weight of between about 22 to 34 kDa, 
 (ii) the protein s activity includes hydrolysis of myo-inositol 1-phosphate to generate inositol and inorganic phosphate, and  
 (iii) (a) specifically binding to an antibody raised against an IMP.18p myo-inositol monophosphatase protein, or immunogenic fragment thereof, consisting of SEQ ID NO:17, or 
 (b) having at least 60% amino acid sequence identity to an IMP.18p myo-inositol monophosphatase protein consisting of SEQ ID NO:17, as measured using a sequence comparison algorithm; or,  
 
 an antisense nucleic acid sequence complementary to at least a portion of the IMP.18p myo-inositol monophosphatase polynucleotide.  
   
     
     
         18 . An organism comprising an exogenous nucleic acid sequence, wherein the nucleic acid specifically hybridizes under stringent conditions to SEQ ID NO:16 or comprises the nucleic acid encoding an IMP.18p myo-inositol monophosphatase protein, said protein defined as follows (i) having a calculated molecular weight of between about 22 to 34 kDa, (ii) the protein's activity includes hydrolysis of myo-inositol 1-phosphate to generate inositol and inorganic phosphate, and 
 (iii) (a) specifically binding to an antibody raised against an IMP.18p myo-inositol monophosphatase protein, or immunogenic fragment thereof, consisting of SEQ ID NO:17, or 
 (b) having at least 60% amino acid sequence identity to an IMP.18p myo-inositol monophosphatase protein consisting of SEQ ID NO:17, as measured using a sequence comparison algorithm; or fragment thereof, has been introduced, and the organism expresses the exogenous nucleic acid as an IMP.18p myo-inositol monophosphatase protein, or fragment thereof.  
   
     
     
         19 . The organism of  claim 17 , wherein the exogenous nucleic acid sequence is translated into an IMP.18p myo-inositol monophosphatase protein which is expressed externally from the organism.  
     
     
         20 . An isolated IMP.18p myo-inositol monophosphatase protein, said protein: 
 (i) having a calculated molecular weight of about 22 to 34 kDa;    (ii) the protein's activity includes hydrolysis of myo-inositol 1-phosphate to generate inositol and inorganic phosphate; and    (v) (a) specifically binding to an antibody raised against a myo-inositol monophosphatase protein, or immunogenic fragment thereof, consisting of SEQ ID NO:17; or 
 (b) having at least 60% amino acid sequence identity to a myo-inositol monophosphatase protein consisting of SEQ ID NO:17, as measured using a sequence comparison algorithm.  
   
     
     
         21 . The isolated IMP.18p myo-inositol monophosphatase protein of  claim 20 , wherein the myo-inositol monophosphatase protein can be found in humans.  
     
     
         22 . The isolated IMP.18p myo-inositol monophosphatase protein of  claim 20 , wherein the calculated molecular weight is about 28 to 29 kDa.  
     
     
         23 . The isolated IMP.18p myo-inositol monophosphatase protein of  claim 20 , wherein the protein has a sequence as set forth in SEQ ID NO:17.  
     
     
         24 . An isolated antibody, specifically immunoreactive under immunologically reactive conditions, to an IMP.18p myo-inositol monophosphatase protein, said protein having the sequence as set forth in SEQ ID NO:17.  
     
     
         25 . An isolated antibody, specifically immunoreactive under immunologically reactive conditions, to a protein defined as follows 
 (i) having a calculated molecular weight of between about 22 to 34 kDa,    (ii) the protein's activity includes hydrolysis of myo-inositol l-phosphate to generate inositol and inorganic phosphate, and    (iii) (a) specifically binding to an antibody raised against an IMP.18p myo-inositol monophosphatase protein, or immunogenic fragment thereof, consisting of SEQ ID NO:17, or 
 (b) having at least 60% amino acid sequence identity to an IMP.18p myo-inositol monophosphatase protein consisting of SEQ ID NO:17, as measured using a sequence comparison algorithm.  
   
     
     
         26 . A pharmaceutical composition comprising an acceptable carrier and an IMP.18p myo-inositol monophosphatase protein as defined by the protein of  claim 20;  an anti-IMP.18p myo-inositol monophosphatase antibody or binding fragment thereof as defined by claims  24  and  25 ; or a polynucleotide encoding an IMP.18p myo-inositol monophosphatase protein as defined by  claim 9 .  
     
     
         27 . A method for quantifying the amount of a myo-inositol monophosphatase in a mammal, comprising: 
 (a) obtaining a cell or tissue sample from the mammal; and    (b) determining the amount of an IMP.18p myo-inositol monophosphatase gene product in the cell or tissue.    
     
     
         28 . A method for detecting the presence of a polynucleotide sequence encoding at least a portion of an IMP.18p myo-inositol monophosphatase in a biological sample, comprising the steps of: 
 a) providing: 
 i) a biological sample suspected of containing a nucleic acid corresponding to the polynucleotide sequence of an IMP.18p myo-inositol monophosphatase;  
 ii) a probe comprising a nucleotide sequence of an IMP.18p myo-inositol monophosphatase, or a fragment thereof capable of hybridizing to a myo-inositol monophosphatase-encoding nucleic acid, from a biological sample;  
   b) combining said nucleic acid-containing biological sample with said probe under conditions such that a hybridization complex is formed between said nucleic acid and said probe; and    c) detecting said hybridization complex.    
     
     
         29 . The method of  claim 28 , wherein, said nucleic acid in said biological sample is ribonucleic acid.  
     
     
         30 . The method of  claim 29 , wherein said detected hybridization complex correlates with expression of an IMP.18p myo-inositol monophosphatase in said biological sample.  
     
     
         31 . A method of determining whether a test compound is a modulator of an IMP.18p myo-inositol monophosphatase activity, said method comprising the steps of: 
 a) providing a composition comprising an IMP.18p myo-inositol monophosphatase protein;    b) contacting the IMP.18p myo-inositol monophosphatase protein with the test compound, and    c) measuring the activity of the IMP.18p myo-inositol monophosphatase, wherein a change in the IMP.18p myo-inositol monophosphatase activity in the presence of the test compound is an indicator of whether the test compound modulates the IMP.18p myo-inositol monophosphatase activity.    
     
     
         32 . The method of  claim 31 , wherein the IMP.18p myo-inositol monophosphatase protein is defined as follows 
 (i) having a calculated molecular weight of between about 22 to 34 kDa,    (ii) the protein's activity includes hydrolysis of myo-inositol 1-phosphate to generate inositol and inorganic phosphate, and    (iii) (a) specifically binding to an antibody raised against an IMP.18p myo-inositol monophosphatase protein, or immunogenic fragment thereof, consisting of SEQ ID NO:17, or 
 (b) having at least 60% amino acid sequence identity to an IMP.18p myo-inositol monophosphatase protein consisting of SEQ ID NO:17, as measured using a sequence comparison algorithm.  
   
     
     
         33 . The method of  claim 31 , wherein the composition comprises a cell.  
     
     
         34 . The method of  claim 31 , wherein the composition comprises an organism.