cDNA for human methylenetetrahydrofolate reductase and uses thereof

• US 20030148323A1
• Filed: 09/04/2002
• Published: 08/07/2003
• Est. Priority Date: 05/26/1994
• Status: Abandoned Application

• Current Assignee: McGill University
• Original Assignee: McGill University
• Inventors: Rozen, Rima
• Application Number:
  US10/235,172
• Publication Number:
  US 20030148323A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12N 9/0026 acting on CH-NH groups of donors (1.5)
• CPC Class Codes: C12N 9/0028 with NAD or NADP as acceptor (1.5.1)
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Y 105/0102 Methylenetetrahydrofolate reductase [NAD(P)H] (1.5.1.20)

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.

Claims

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.