Insights into Severe 5,10-Methylenetetrahydrofolate Reductase Deficiency: Molecular Genetic and Enzymatic Characterization of 76 Patients

Human Mutation

Volumn 36, Issue 6, 2015, Pages 611-621

  Burda, Patricie ^a   Schäfer, Alexandra ^a   Suormala, Terttu ^a   Rummel, Till ^b   Bürer, Céline ^a   Heuberger, Dorothea ^a   Frapolli, Michele ^a   Giunta, Cecilia ^a   Sokolová, Jitka ^c   Vlášková, Hana ^c   Kožich, Viktor ^c   Koch, Hans Georg ^b,d   Fowler, Brian ^a   Froese, D Sean ^a,e   Baumgartner, Matthias R ^a,e  

^a UNIVERSITY CHILDREN S HOSPITAL   (Switzerland)

^b UNIVERSITY HOSPITAL MÜNSTER   (Germany)

^c Charles University in Prague and General University Hospital in Prague   (Czech Republic)

^d KLINIKUM BRAUNSCHWEIG   (Germany)

^e UNIVERSITY OF ZURICH   (Switzerland)

Author keywords

Enzyme kinetics; Homocystinuria; Methylenetetrahydrofolate; MTHFR

Indexed keywords

5,10 METHYLENETETRAHYDROFOLATE REDUCTASE (FADH2); FLAVINE ADENINE NUCLEOTIDE; METHYLENETETRAHYDROFOLIC ACID; NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; RIBOFLAVIN; METHYLENETETRAHYDROFOLATE REDUCTASE (NADPH2);

5' UNTRANSLATED REGION; ALLELE; AMINO TERMINAL SEQUENCE; ARTICLE; CARBOXY TERMINAL SEQUENCE; CELL LYSATE; CELL MUTANT; CELL STRUCTURE; CONTROLLED STUDY; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME ANALYSIS; ENZYME ASSAY; ENZYME DEFICIENCY; ENZYME KINETICS; EXON; EXON SKIPPING; FEMALE; FIBROBLAST; FIBROBLAST CULTURE; GENE FREQUENCY; GENE MUTATION; GENETIC ANALYSIS; GENOTYPE; HAPLOTYPE; HEAT TREATMENT; HUMAN; HUMAN CELL; INTRON; MALE; MISSENSE MUTATION; MOLECULAR GENETICS; MUTATIONAL ANALYSIS; NONSENSE MUTATION; PRIORITY JOURNAL; SINGLE NUCLEOTIDE POLYMORPHISM; STOP CODON; ALTERNATIVE RNA SPLICING; DEFICIENCY; ENZYME ACTIVATION; GENETIC ASSOCIATION STUDY; GENETICS; HOMOCYSTINURIA; KINETICS; METABOLISM; MUSCLE SPASTICITY; MUTATION; PROTEIN STABILITY; PSYCHOTIC DISORDERS;

ALLELES; ALTERNATIVE SPLICING; ENZYME ACTIVATION; EXONS; FIBROBLASTS; GENETIC ASSOCIATION STUDIES; HOMOCYSTINURIA; HUMANS; INTRONS; KINETICS; METHYLENETETRAHYDROFOLATE REDUCTASE (NADPH2); MUSCLE SPASTICITY; MUTATION; POLYMORPHISM, SINGLE NUCLEOTIDE; PROTEIN STABILITY; PSYCHOTIC DISORDERS;

EID: 84929515859     PISSN: 10597794     EISSN: 10981004     Source Type: Journal    
DOI: 10.1002/humu.22779     Document Type: Article

References (50)

1. Bathgate D, Yu-Wai-Man P, Webb B, Taylor RW, Fowler B, Chinnery PF. 2012. Recessive spastic paraparesis associated with complex I deficiency due to MTHFR mutations. J Neurol Neurosurg Psychiatry 83:115.
2. Ben-Shachar S, Zvi T, Rolfs A, Breda Klobus A, Yaron Y, Bar-Shira A, Orr-Urtreger A. 2012. A founder mutation causing a severe methylenetetrahydrofolate reductase (MTHFR) deficiency in Bukharian Jews. Mol Genet Metab 107:608-610.
3. Brattstrom L, Wilcken DE, Ohrvik J, Brudin L. 1998. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation 98:2520-2526.
4. Coelho D, Kim JC, Miousse IR, Fung S, du Moulin M, Buers I, Suormala T, Burda P, Frapolli M, Stucki M, Nurnberg P, Thiele H, et al. 2012. Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. Nat Genet 44:1152-1155.
5. Crushell E, O'Leary D, Irvine AD, O'Shea A, Mayne PD, Reardon W. 2012. Methylenetetrahydrofolate reductase (MTHFR) deficiency presenting as a rash. Am J Med Genet A 158A:2254-2257.
6. Daubner SC, Matthews RG. 1982. Purification and properties of methylenetetrahydrofolate reductase from pig liver. J Biol Chem 257:140-145.
7. Forges T, Chery C, Audonnet S, Feillet F, Gueant JL. 2010. Life-threatening methylenetetrahydrofolate reductase (MTHFR) deficiency with extremely early onset: characterization of two novel mutations in compound heterozygous patients. Mol Genet Metab 100:143-148.
8. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, vanden Heuvel LP, Rozen R. 1995. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111-113.
9. Giunta C, Superti-Furga A, Spranger S, Cole WG, Steinmann B. 1999. Ehlers-Danlos syndrome type VII: clinical features and molecular defects. J Bone Joint Surg Am 81:225-238.
10. Goyette P, Christensen B, Rosenblatt DS, Rozen R. 1996. Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR. Am J Hum Genet 59:1268-1275.
11. Goyette P, Frosst P, Rosenblatt DS, Rozen R. 1995. Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet 56:1052-1059.
12. Goyette P, Pai A, Milos R, Frosst P, Tran P, Chen Z, Chan M, Rozen R. 1998. Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome 9:652-656.
13. Goyette P, Rozen R. 2000. The thermolabile variant 677C→T can further reduce activity when expressed in cis with severe mutations for human methylenetetrahydrofolate reductase. Hum Mutat 16:132-138.
14. Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R. 1994. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 7:195-200.
15. Guenther BD, Sheppard CA, Tran P, Rozen R, Matthews RG, Ludwig ML. 1999. The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nat Struct Biol 6:359-365.
16. Hanson NQ, Aras O, Yang F, Tsai MY. 2001. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease. Clin Chem 47:661-666.
17. Hustad S, Ueland PM, Vollset SE, Zhang Y, Bjorke-Monsen AL, Schneede J. 2000. Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism. Clin Chem 46:1065-1071.
18. Jencks DA, Mathews RG. 1987. Allosteric inhibition of methylenetetrahydrofolate reductase by adenosylmethionine. Effects of adenosylmethionine and NADPH on the equilibrium between active and inactive forms of the enzyme and on the kinetics of approach to equilibrium. J Biol Chem 262:2485-2493.
19. Kluijtmans LA, Wendel U, Stevens EM, vanden Heuvel LP, Trijbels FJ, Blom HJ. 1998. Identification of four novel mutations in severe methylenetetrahydrofolate reductase deficiency. Eur J Hum Genet 6:257-265.
20. Lee MN, Takawira D, Nikolova AP, Ballou DP, Furtado VC, Phung NL, Still BR, Thorstad MK, Tanner JJ, Trimmer EE. 2009. Functional role for the conformationally mobile phenylalanine 223 in the reaction of methylenetetrahydrofolate reductase from Escherichia coli. Biochemistry 48:7673-7685.
21. Litzkas P, Jha KK, Ozer HL. 1984. Efficient transfer of cloned DNA into human diploid cells: protoplast fusion in suspension. Mol Cell Biol 4:2549-2552.
22. Lossos A, Teltsh O, Milman T, Meiner V, Rozen R, Leclerc D, Schwahn BC, Karp N, Rosenblatt DS, Watkins D, Shaag A, Korman SH, et al. 2014. Severe methylenetetrahydrofolate reductase deficiency: clinical clues to a potentially treatable cause of adult-onset hereditary spastic paraplegia. JAMA Neurol 71:901-904.
23. Marini NJ, Gin J, Ziegle J, Keho KH, Ginzinger D, Gilbert DA, Rine J. 2008. The prevalence of folate-remedial MTHFR enzyme variants in humans. Proc Natl Acad Sci USA 105:8055-8060.
24. Martin YN, Salavaggione OE, Eckloff BW, Wieben ED, Schaid DJ, Weinshilboum RM. 2006. Human methylenetetrahydrofolate reductase pharmacogenomics: gene resequencing and functional genomics. Pharmacogenet Genomics 16:265-277.
25. Matthews RG, Vanoni MA, Hainfeld JF, Wall J. 1984. Methylenetetrahydrofolate reductase. Evidence for spatially distinct subunit domains obtained by scanning transmission electron microscopy and limited proteolysis. J Biol Chem 259:11647-11650.
26. Markham AF. 1989. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res 17:2503-2516.
27. Newton CR, Graham A, Heptinstall LE, Powell SJ, Summers C, Kalsheker N, Smith JC, Markham AF. 1989. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res 17:2503-16.
28. Pavlikova M, Sokolova J, Janosikova B, Melenovska P, Krupkova L, Zvarova J, Kozich V. 2012. Rare allelic variants determine folate status in an unsupplemented European population. J Nutr 142:1403-1409.
29. Pejchal R, Campbell E, Guenther BD, Lennon BW, Matthews RG, Ludwig ML. 2006. Structural perturbations in the Ala → Val polymorphism of methylenetetrahydrofolate reductase: how binding of folates may protect against inactivation. Biochemistry 45:4808-4818.
30. Pejchal R, Sargeant R, Ludwig ML. 2005. Structures of NADH and CH3-H4folate complexes of Escherichia coli methylenetetrahydrofolate reductase reveal a spartan strategy for a ping-pong reaction. Biochemistry 44:11447-11457.
31. Rady PL, Szucs S, Grady J, Hudnall SD, Kellner LH, Nitowsky H, Tyring SK, Matalon RK. 2002. Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A. Am J Med Genet 107:162-168.
32. Richard E, Desviat LR, Ugarte M, Perez B. 2013. Oxidative stress and apoptosis in homocystinuria patients with genetic remethylation defects. J Cell Biochem 114:183-191.
33. Rummel T, Suormala T, Haberle J, Koch HG, Berning C, Perrett D, Fowler B. 2007. Intermediate hyperhomocysteinaemia and compound heterozygosity for the common variant c.677C>T and a MTHFR gene mutation. J Inherit Metab Dis 30:401.
34. Schiff M, Benoist JF, Tilea B, Royer N, Giraudier S, Ogier de Baulny H. 2011. Isolated remethylation disorders: do our treatments benefit patients? J Inherit Metab Dis 34:137-145.
35. Shan X, Wang L, Hoffmaster R, Kruger WD. 1999. Functional characterization of human methylenetetrahydrofolate reductase in Saccharomyces cerevisiae. J Biol Chem 274:32613-3268.
36. Sibani S, Leclerc D, Weisberg IS, O'Ferrall E, Watkins D, Artigas C, Rosenblatt DS, Rozen R. 2003. Characterization of mutations in severe methylenetetrahydrofolate reductase deficiency reveals an FAD-responsive mutation. Hum Mutat 21:509-520.
37. Strauss KA, Morton DH, Puffenberger EG, Hendrickson C, Robinson DL, Wagner C, Stabler SP, Allen RH, Chwatko G, Jakubowski H, Niculescu MD, Mudd SH. 2007. Prevention of brain disease from severe 5, 10-methylenetetrahydrofolate reductase deficiency. Mol Genet Metab 91:165-175.
38. Sumner J, Jencks DA, Khani S, Matthews RG. 1986. Photoaffinity labeling of methylenetetrahydrofolate reductase with 8-azido-S-adenosylmethionine. J Biol Chem 261:7697-7700.
39. Suormala T, Gamse G, Fowler B. 2002. 5, 10-Methylenetetrahydrofolate reductase (MTHFR) assay in the forward direction: residual activity in MTHFR deficiency. Clin Chem 48:835-843.
40. Tonetti C, Saudubray JM, Echenne B, Landrieu P, Giraudier S, Zittoun J. 2003. Relations between molecular and biological abnormalities in 11 families from siblings affected with methylenetetrahydrofolate reductase deficiency. Eur J Pediatr 162:466-475.
41. Tran P, Leclerc D, Chan M, Pai A, Hiou-Tim F, Wu Q, Goyette P, Artigas C, Milos R, Rozen R. 2002. Multiple transcription start sites and alternative splicing in the methylenetetrahydrofolate reductase gene result in two enzyme isoforms. Mamm Genome 13:483-492.
42. Tsuji M, Takagi A, Sameshima K, Iai M, Yamashita S, Shinbo H, Furuya N, Kurosawa K, Osaka H. 2011. 5, 10-Methylenetetrahydrofolate reductase deficiency with progressive polyneuropathy in an infant. Brain Dev 33:521-524.
43. Urreizti R, Moya-Garcia AA, Pino-Angeles A, Cozar M, Langkilde A, Fanhoe U, Esteves C, Arribas J, Vilaseca MA, Perez-Duenas B, Pineda M, Gonzalez V, et al. 2010. Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency. Clin Genet 78:441-448.
44. vander Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, vanden Heuvel LP, Blom HJ. 1998. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62:1044-1051.
45. vander Put NM, vanden Heuvel LP, Steegers-Theunissen RP, Trijbels FJ, Eskes TK, Mariman EC, den Heyer M, Blom HJ. 1996. Decreased methylene tetrahydrofolate reductase activity due to the 677C→T mutation in families with spina bifida offspring. J Mol Med (Berl) 74:691-694.
46. Watkins D, Rosenblatt DS. 2012. Update and new concepts in vitamin responsive disorders of folate transport and metabolism. J Inherit Metab Dis 35:665-670.
47. Watkins D, Rosenblatt DS. 2014. Inherited disorders of folate and cobalamin transport and metabolism. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson M, Mitchell G, editors. The online metabolic and molecular bases of inherited disease. Online Edition. New York: McGraw-Hill.
48. Wilson CP, McNulty H, Ward M, Strain JJ, Trouton TG, Hoeft BA, Weber P, Roos FF, Horigan G, McAnena L, Scott JM. 2013. Blood pressure in treated hypertensive individuals with the MTHFR 677TT genotype is responsive to intervention with riboflavin: findings of a targeted randomized trial. Hypertension 61:1302-1308.
49. Winkelmayer WC, Sunder-Plassmann G, Huber A, Fodinger M. 2004. Patterns of co-occurrence of three single nucleotide polymorphisms of the 5, 10-methylenetetrahydrofolate reductase gene in kidney transplant recipients. Eur J Clin Invest 34:613-618.
50. Yamada K, Chen Z, Rozen R, Matthews RG. 2001. Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Proc Natl Acad Sci USA 98:14853-14858.