cDNA for human methylenetetrahydrofolate reductase and uses thereof

Abstract

The invention features methods for diagnosing subjects at risk for or suffering from a disease or disorder, such as a psychosis. Methods are also provided for selecting a preferred therapy for a particular subject or group of subjects.

1 . A method diagnosing a schizophrenia in a subject, said method comprising the steps of: 
 (a) analyzing the methylenetetrahydrofolate reductase (MTHFR) nucleic acid in a sample obtained from said subject; and    (b) determining the presence of at least one heterozygous MTHFR mutant allele in said subject, wherein said mutant allele encodes an MTHFR protein with reduced activity or reduced thermal stability, and wherein the presence of said mutant allele is indicative of said subject having said schizophrenia.    
     
     
         2 . The method of  claim 1 , wherein said mutant allele encodes an MTHFR protein with reduced activity.  
     
     
         3 . The method of  claim 1 , wherein said mutant allele leads to a decreased level of folate.  
     
     
         4 . The method of  claim 1 , wherein said mutant allele leads to an increased level of homocysteine.  
     
     
         5 . The method of  claim 1 , wherein said mutant allele leads to a decreased level of S-adenosylmethionine or a decreased level of methylation reactions.  
     
     
         6 . The method of  claim 1 , wherein said mutant allele comprises at least one mutation selected from the group consisting of a G/A mutation at position 167, a G/A mutation at position 482, a C/T mutation a position 559, a C/T mutation at position 692, a C/T mutation at position 764, a G/A mutation at position 792+1, a C/T mutation at position 985, a C/T mutation at position 1015, a C/T mutation at position 1081, and an A/C mutation at position 1298.  
     
     
         7 . The method of  claim 6 , wherein said mutant allele comprises an A/C mutation at position 1298.  
     
     
         8 . A method of determining a risk for a schizophrenia or propensity thereto in a subject, said method comprising the steps of: 
 (a) analyzing the MTHFR nucleic acid in a sample obtained from said subject; and    (b) determining the presence of at least one heterozygous MTHFR mutant allele in said subject, wherein said mutant allele encodes an MTHFR protein with reduced activity or reduced thermal stability, and wherein the presence of said mutant allele is is indicative of a risk for a schizophrenia or propensity thereto in said subject.    
     
     
         9 . The method of  claim 8 , wherein said mutant allele encodes an MTHFR protein with reduced activity.  
     
     
         10 . The method of  claim 8 , wherein said mutant allele leads to a decreased level of folate.  
     
     
         11 . The method of  claim 8 , wherein said mutant allele leads to an increased level of homocysteine.  
     
     
         12 . The method of  claim 8 , wherein said mutant allele leads to a decreased level of S-adenosylmethionine or a decreased level of methylation reactions.  
     
     
         13 . The method of  claim 8 , wherein said mutant allele comprises 
 at least one mutation selected from the group consisting of a G/A mutation at position 167, a G/A mutation at position 482, a C/T mutation a position 559, a C/T mutation at position 692, a C/T mutation at position 764, a G/A mutation at position 792+1, a C/T mutation at position 985, a C/T mutation at position 1015, a C/T mutation at position 1081, and an A/C mutation at position 1298.    
     
     
         14 . The method of  claim 13 , wherein said mutant allele comprises an A/C mutation at position 1298.  
     
     
         15 . A method of diagnosing a schizophrenia in a subject, said method comprising the steps of: 
 (a) analyzing the MTHFR nucleic acid in a sample obtained from said subject; and    (b) determining the presence of a heterozygous MTHFR mutation at position 677 and the presence of at least one other MTHFR mutation at a position other than 677, wherein said mutations lead to reduced MTHFR activity or thermal stability, and wherein the presence of at least one of said mutations or the combination of said mutations is indicative of said subject having said schizophrenia.    
     
     
         16 . The method of  claim 15 , wherein said nucleic acid having said MTHFR mutation at position 677 and said MTHFR mutation at a position other than 677 encodes an MTHFR protein with reduced activity.  
     
     
         17 . The method of  claim 15 , wherein said mutations lead to a decreased level of folate.  
     
     
         18 . The method of  claim 15 , wherein said mutations lead to an increased level of homocysteine.  
     
     
         19 . The method of  claim 15 , wherein said mutations lead to a decreased level of S-adenosylmethionine or a decreased level of methylation reactions.  
     
     
         20 . The method of  claim 15 , wherein said MTHFR mutation at a position other than 677 is selected from the group consisting of a G/A mutation at position 167, a G/A mutation at position 482, a C/T mutation a position 559, a C/T mutation at position 692, a C/T mutation at position 764, a G/A mutation at position 792+1, a C/T mutation at position 985, a C/T mutation at position 1015, a C/T mutation at position 1081, and an A/C mutation at position 1298.  
     
     
         21 . The method of  claim 20 , wherein said MTHFR mutation at a position other than 677 is an A/C mutation at position 1298.  
     
     
         22 . A method of diagnosing a risk for a schizophrenia or propensity thereto in a subject, said method comprising the steps of: 
 (a) analyzing the MTHFR nucleic acid in a sample obtained from said subject; and    (b) determining the presence of a heterozygous MTHFR mutation at position 677 and the presence of at least one other MTHFR mutation at a position other than 677, wherein said mutations lead to reduced MTHFR activity or thermal stability, and wherein the presence of at least one of said mutations or the combination of said mutations is indicative of a risk for a schizophrenia or propensity thereto in said subject.    
     
     
         23 . The method of  claim 22 , wherein said nucleic acid having said MTHFR mutation at position 677 and said MTHFR mutation at a position other than 677 encodes an MTHFR protein with reduced activity.  
     
     
         24 . The method of  claim 22 , wherein said mutations lead to a decreased level of folate.  
     
     
         25 . The method of  claim 22 , wherein said mutations lead to an increased level of homocysteine.  
     
     
         26 . The method of  claim 22 , wherein said mutations lead to a decreased level of S-adenosylmethionine or a decreased level of methylation reactions.  
     
     
         27 . The method of  claim 22 , wherein said MTHFR mutation at a position other than 677 is selected from the group consisting of a G/A mutation at position 167, a G/A mutation at position 482, a C/T mutation a position 559, a C/T mutation at position 692, a C/T mutation at position 764, a G/A mutation at position 792+1, a C/T mutation at position 985, a C/T mutation at position 1015, a C/T mutation at position 1081; and an A/C mutation at position 1298.  
     
     
         28 . The method of  claim 27 , said MTHFR mutation at a position other than 677 is an A/C mutation at position 1298.