Human methionine synthase reductase: cloning, and methods for evaluating risk of neural tube deffects, cardiovascular disease, cancer and Down's Syndrome

Abstract

The invention features a novel gene encoding methionine synthase reductase. The invention also features a method for detecting an increased likelihood of hyperhomocysteinemia and, in turn, an increased or decreased likelihood of neural tube defects, cardiovascular disease, Down's Syndrome or cancer. The invention also features therapeutic methods for treating and/or reducing the risk of cardiovascular disease, Down's Syndrome, cancer, or neural tube defects. Also provided are the sequences of the human methionine synthase reductase gene and protein and compounds and kits for performing the methods of the invention.

1 . A method for detecting an increased risk of cancer in a mammal, said method comprising detecting the presence of a homozygous methionine synthase reductase (MTRR) polymorphism in said mammal, wherein detection of said polymorphism indicates said mammal has an increased risk of developing cancer.  
     
     
         2 . The method of  claim 1 , wherein said polymorphic MTRR is detected by analyzing nucleic acid from said mammal.  
     
     
         3 . The method of  claim 2 , wherein said nucleic acid is genomic deoxyribonucleic acid (DNA).  
     
     
         4 . The method of  claim 2 , wherein said nucleic acid is complementary DNA (cDNA).  
     
     
         5 . The method of  claim 1 , wherein said polymorphism is selected from the group consisting of: 
 (a) a G instead of an A at position 66 relative to the first nucleotide of the start codon of MTRR,    (b) a G instead of an A at position 110 relative to the first nucleotide of the start codon of MTRR,    (c) a deletion of 4 nucleotides starting from position 1675 (nucleotides 1675-1678) relative to the first nucleotide of the start codon of MTRR, and    (d) a deletion of 3 nucleotides starting from nucleotide 1726 (nucleotides 1726-1728) relative to the first nucleotide of the start codon of MTRR.    
     
     
         6 . The method of  claim 2 , wherein said polymorphic MTRR is detected by a method comprising: 
 a) PCR-amplifying a segment of MTRR nucleic acid from said future female parent, said embryo, or said fetus using primers MSG108S (SEQ ID NO:    49) and AD292 (SEQ ID NO: 50), and    b) digesting the product of the PCR amplification reaction with the restriction enzyme Nde I, wherein a PCR product that is digested by Nde I indicates the presence of said polymorphic MTRR.    
     
     
         7 . The method of  claim 1 , wherein said polymorphic MTRR is detected by analyzing MTRR polypeptide from said mammal.  
     
     
         8 . The method of  claim 1 , said method further comprising detecting the presence of a polymorphic methylenetetrahydrofolate reductase (MTHFR) in said mammal, wherein detection of said polymorphic MTHFR indicates an increased risk of developing cancer.  
     
     
         9 . The method of  claim 8 , wherein said polymorphic MTHFR has a T instead of a C at a nucleotide position equivalent to position 677 of SEQ ID NO: 51.  
     
     
         10 . The method of  claim 8 , wherein said polymorphic MTHFR is detected by analyzing nucleic acid from said mammal.  
     
     
         11 . The method of  claim 8 , wherein said polymorphic MTHFR is detected by analyzing MTHFR polypeptide from said mammal.  
     
     
         12 . The method of  claim 1 , wherein said polymorphic MTRR contains a methionine instead of an isoleucine at amino acid position 22.  
     
     
         13 . The method of  claim 1 , wherein said cancer is colon cancer.  
     
     
         14 . The method of  claim 1 , wherein said mammal is human.  
     
     
         15 . A method for detecting an increased risk of a folate/cobalamin metabolic disorder in a mammal, said method comprising detecting the presence of a homozygous MTRR polymorphism that indicates an increased risk of a folate/cobalamin metabolic disorder in said mammal, wherein said polymorphism comprises 
 (a) a G instead of an A at position 66 relative to the first nucleotide of the start codon of MTRR,    (b) a deletion of 4 nucleotides starting from position 1675 (nucleotides 1675-1678) relative to the first nucleotide of the start codon of MTRR, or    (c) a deletion of 3 nucleotides starting from nucleotide 1726 (nucleotides 1726-1728) relative to the first nucleotide of the start codon of MTRR.    
     
     
         16 . The method of  claim 15 , wherein said folate/cobalamin metabolic disorder is megablastic anemia, developmental delay, hyperhomocysteinuria, or hypomethionemia.  
     
     
         17 . The method of  claim 15 , wherein said mammal is human.  
     
     
         18 . The method of  claim 15 , further comprising measuring the level of cobalamin in said mammal.  
     
     
         19 . The method of  claim 15 , wherein said polymorphic MTRR is detected by analyzing nucleic acid from said mammal.