Methods for detecting human methylenetetrahydrofolate reductase allelic variants

• US 6,528,259 B1
• Filed: 09/13/2000
• Issued: 03/04/2003
• Est. Priority Date: 05/26/1994
• Status: Expired due to Term

• Current Assignee: McGill University
• Original Assignee: McGill University
• Inventors: Goyette, Philippe, Rozen, Rima
• Primary Examiner(s): Myers, Carla J.
• Application Number:
  US09/660,872
• Time in Patent Office: 902 Days
• Field of Search: 435/6, 435/23, 435/91.2, 536/23.5, 536/24.31, 530/350, 514/1.2, 514/250
• US Class Current: 435/5
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• 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: 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

Abstract

Provided herein is a heretofore unknown isolated nucleic acid molecule which encodes human methylenetetrahydrofolate reducatase, along with an amino acid sequence of methylenetetrahydrofolate reductase, and a cDNA probe for human methylenetetrahydrofolate reductase. Also provided are a molecule description of mutations in humans resulting in a phenotype having reduced levels of methylenetetrahydrofolate reductase, and methods of diagnosing methylenetetrahydrofolate reductase deficiency in a human.

Claims

1. A method for treating an individual having an MTHFR allele variant, said method comprising:

(a) analyzing a nucleic acid sample obtained from said individual to determine whether said sample comprises at least one MTHFR allele variant, said variant leading to a decrease in MTHFR activity; and

(b) treating said individual having said MTHFR allele variant.

2. The method of claim 1, wherein said MTHFR allele variant is selected from the group consisting of 167G/A, 482G/A, 559C/T, 677C/T, 692C/T, 764C/T, 792+1G/A, 985C/T, 1015C/T, and 1081C/T.

3. The method of claim 1, wherein said MTHFR allele variant is 677C/T.

4. The method of claim 1, wherein said MTHFR allele variant is associated with a disorder selected from the group consisting of cardiovascular disorders, coronary and arterial disorders, cancer, osteoporosis, and neurological disorders.

5. The method of claim 1, wherein said MTHFR allele variant is associated with a neural tube defect.

6. The method of claim 1, wherein said MTHFR allele variant is associated with a disorder influenced by folic acid metabolism.

7. The method of claim 1, wherein said treatment is selected from the group consisting of folate and folic acid.

34. The method of claim 1 or 8, wherein said individual is treated with a treatment that affects folic acid metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

35. The method of claim 1, 8, or 14 wherein said individual is treated with a treatment for a disorder associated with reduced MTHFR activity, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

36. The method of claim 1, 8, or 14, wherein said individual is treated with a treatment for a disorder associated with said MTHFR allele variant, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

37. The method of claim 34, wherein said treatment is for a disorder selected from the group consisting of cardiovascular disorders, coronary and arterial disorders, cancer, osteoporosis, and neurological disorders, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

8. A method for treating an individual having an MTHFR allele variant, said method comprising:

(a) analyzing a nucleic acid sample obtained from said individual to determine whether said sample comprises the MTHFR allele variant 1317T/C, said variant leading to a decrease in MTHFR activity; and

(b) treating said individual having said MTHFR allele variant.

9. The method of claim 8, wherein said MTHFR allele variant is associated with a disorder selected from the group consisting of cardiovascular disorders, coronary and arterial disorders, cancer, osteoporosis, and neurological disorders.

10. The method of claim 8, wherein said MTHFR allele variant is associated with a neural tube defect.

11. The method of claim 8, wherein said MTHFR allele variant is associated with a disorder influenced by folic acid metabolism.

12. The method of claim 8, wherein said treatment is selected from the group consisting of antibiotics and antiepileptic agents, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

13. The method of claim 8, wherein said treatment is selected from the group consisting of folate and folic acid.

52. The method of claim 12 or 27, wherein said treatment is selected from the group consisting of antiepileptic agents, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

14. A method for treating an individual having an MTHFR allele variant, said method comprising:

(a) analyzing a nucleic acid sample obtained from said individual to determine whether said sample comprises at least one MTHFR allele variant, said variant leading to a decrease in MTHFR activity; and

(b) treating said individual having said MTHFR allele variant with a treatment that affects folate acid metabolism and leads to an increased level of folate or to a decreased level of homocysteine, wherein said treatment is for a disorder selected from the group consisting of cardiovascular disorders, coronary and arterial disorders, osteoporosis, and neurological disorders.

15. The method of claim 14, wherein said MTHFR allele variant is selected from the group consisting of 167G/A, 482G/A, 559C/T, 677C/T, 692C/T, 764C/T, 792+1G/A, 985C/T, 1015C/T, and 1081C/T.

16. The method of claim 14, wherein said MTHFR allele variant is 677C/T.

17. The method of claim 14, wherein said MTHFR allele variant is associated with a disorder selected from the group consisting of cardiovascular disorders, coronary and arterial disorders, cancer, osteoporosis, and neurological disorders.

18. The method of claim 14, wherein said MTHFR allele variant is associated with a neural tube defect.

19. The method of claim 14, wherein said MTHFR allele variant is associated with a disorder influenced by folic acid metabolism.

24. The method of claim 19, wherein said treatment is selected from the group consisting of folate and folic acid.

20. A method for selecting a treatment affecting folic acid metabolism for an individual having an MTHFR allele variant, said method comprising:

(a) analyzing a nucleic acid sample obtained from said individual to determine whether said sample comprises at least one MTHFR allele variant, said variant leading to a decrease in MTHFR activity; and

(b) selecting a treatment that affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

21. The method of claim 20, wherein said MTHFR allele variant correlates with increased or decreased drug responsiveness to a treatment selected from the group consisting of antibiotics and antiepileptic agents, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

22. The method of claim 20, wherein said MTHFR allele variant is selected from the group consisting of 167G/A, 482G/A, 599C/T, 677C/T, 692C/T, 746C/T, 792+1A/T, 958C/T, 1015C/T, and 1081C/T.

23. The method of claim 20, wherein said MTHFR allele variant is 677C/T.

38. The method of claim 20, 25, 29, or 32, wherein said treatment is for a disorder associated with reduced MTHFR activity, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

39. The method of claim 20, 25, 29, or 32, wherein said treatment is for a disorder associated with said MTHFR allele variant, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

40. The method of claim 20, 25, 29, or 33, wherein said MTHFR allele variant is associated with a disorder influenced by folic acid metabolism.

41. The method of claim 20 or 25, wherein said MTHFR allele variant is associated with a disorder selected from the group consisting of cardiovascular disorders, coronary and arterial disorders, cancer, osteoporosis, and neurological disorders.

42. The method of claim 20 or 25, wherein said MTHFR allele variant correlates with increased or decreased drug responsiveness to folate or folic acid.

43. The method of claim 20 or 25, wherein said MTHFR allele variant correlates with increased or decreased drug responsiveness to said treatment, wherein said treatment is for a disorder selected from the group consisting of cardiovascular disorders, coronary and arterial disorders, osteoporosis, and neurological disorders, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

45. The method of claim 21, 25, or 33, wherein said MTHFR allele variant correlates with increased drug responsiveness to said a treatment, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

46. The method of claim 20 or 25, wherein said treatment is for a disorder selected from the group consisting of cardiovascular disorders, coronary and arterial disorders, osteoporosis, and neurological disorders, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

51. The method of claim 21 or 26, wherein said treatment is selected from the group consisting of antiepileptic agents, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

25. A method for selecting a treatment affecting folate metabolism for an individual having an MTHFR allele variant, said method comprising:

(a) analyzing a nucleic acid sample obtained from said individual to determine whether said sample comprises the MTHFR allele variant 1317T/C, said variant leading to a decrease in MTHFR activity; and

(b) selecting a treatment that affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

26. The method of claim 25, wherein said MTHFR allele variant correlates with increased or decreased drug responsiveness to a treatment selected from the group consisting of antibiotics and antiepileptic agents, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

27. The method of claim 25, wherein said treatment is selected from the group consisting of antibiotics, antiepileptic agents, and antiarthritic agents, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

28. The method of claim 25, wherein said treatment is selected from the group consisting of folate and folic acid.

44. The method of claim 25, wherein said MTHFR allele variant correlates with increased or decreased drug responsiveness to a treatment selected from the group consisting of antiarthritic agents, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

29. A method for selecting a treatment affecting folate metabolism for an individual having an MTHFR allele variant, said method comprising:

(a) analyzing a nucleic acid sample obtained from said individual to determine whether said sample comprises at least one MTHFR allele variant, said variant leading to a decrease in MTHFR activity; and

(b) selecting a treatment that affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine, wherein said treatment is for a disorder selected from the group consisting of cardiovascular disorders, coronary and arterial disorders, osteoporosis, and neurological disorders.

30. The method of claim 29, wherein said MTHFR allele variant correlates with increased or decreased drug responsiveness to said treatment, and wherein said treatment affects folate metabolism and leads to an increased-level of folate or to a decreased level of homocysteine.

31. The method of claim 29, wherein said MTHFR allele variant is selected from the group consisting of 167G/A, 482G/A, 559C/T, 677C/T, 692C/T, 764C/T, 792+1G/A, 985C/T, 1015C/T, and 1081C/T.

32. The method of claim 29, wherein said MTHFR allele variant is 677C/T.

33. A method for selecting a treatment that has increased or decreased drug responsiveness in an individual having an MTHFR allele variant, said method comprising:

(a) analyzing a nucleic acid sample obtained from said individual to determine whether said sample comprises at least one MTHFR allele variant, said variant leading to a decrease in MTHFR activity, and said variant being correlated to increased or decreased drug responsiveness to an antiarthritic agent; and

(b) selecting a treatment known to have increased or decreased drug responsiveness in an individual having said MTHFR allele, wherein said treatment is selected from the group consisting of antiarthritic agents, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

47. The method of claim 33 or 44, wherein said treatment is methotrexate, and wherein said treatment affects folate metabolism and leads to an increased level of folate or to a decreased level of homocysteine.

48. The method of claim 33, wherein said MTHFR allele variant is selected from the group consisting of 167G/A, 482G/A, 559C/T, 677C/T, 692C/T, 764C/T, 792+1G/A 985C/T, 1015C/T, and 1081C/T.

49. The method of claim 48, wherein said MTHFR allele variant is 677C/T.

50. The method of claim 48, wherein said MTHFR allele variant is selected from the group consisting of 167G/A, 482G/A, 559C/T, 692C/T, 764C/T, 792+1G/A, 985C/T, 1015C/T, and 1081C/T.