Methylenetetrahydrofolate reductase gene polymorphisms in Egyptian Turner Syndrome patients
Languages of publication
Background: Folate metabolism dysfunctions can result in DNA hypomethylation and abnormal chromosome segregation. Two common polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) encoding gene (C677T and A1298C) reduce MTHFR activity, but when associated with aneuploidy, the results are conflicting. Turner Syndrome (TS) is an interesting model for investigating the association between MTHFR gene polymorphisms and nondisjunction because of the high frequency of chromosomal mosaicism in this syndrome. Objective: To investigate the association of MTHFR gene C677T and A1298C polymorphisms in TS patients and their mothers and to correlate these polymorphisms with maternal risk of TS offspring. Subjects and Methods: MTHFR C677T and A1298C polymorphisms were genotyped in 33 TS patients, their mothers and 15 healthy females with their mothers as controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing technique. Results: Genotype and allele frequencies of both C677T and A1298C were not significantly different between TS cases and controls. There were no significant differences in C677T genotype distribution between the TS mothers and controls (p=1). The MTHFR 1298AA and 1298AC genotypes were significantly increased in TS mothers Vs. control mothers (p=0.002). The C allele frequency of the A1298C polymorphism was significantly different between the TS mothers and controls (p=0.02). The association of A1298C gene polymorphism in TS patients was found to increase with increasing age of both mothers (p=0.026) and fathers (p=0.044) of TS cases. Conclusion: Our findings suggest a strong association between maternal MTHFR A1298C and risk of TS in Egypt.
- Bosco P, Anello G, Barone C, Namour F, Caraci F (2003) Methionine synthase (MTR) 2756 (A→G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome. Am J Med Genet 121A: 219-224.
- Chango A, Fillon-Emery N, Mircher C, Bléhaut H, Lambert D, Herbeth B (2005) No association between common polymorphisms in genes of folate and homocysteine metabolism and the risk of Down's syndrome among French mothers. Br J Nutr 94: 166-169.
- Elsheikh M, Dunger DB, Conway GS, Wass JH (2002) Turner's syndrome in adulthood. Endocr Rev 23: 120-140.
- Finkelstein JD (1990) Methionine metabolism in mammals. J Nutr Biochem 1: 228-237.
- Frias JL, Davenport ML (2003) Health supervision for children with Turner syndrome. Pediatrics 111: 692-670.
- Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10: 111-113.
- Gosden CM, Davidson C, Robertson M (1992) Lymphocyte culture. In Human Cytogenetics: A Practical Approach, Rooney DE, Czepulkowski BH eds, 2nd edn, pp 31-54. IRL Press, Oxford.
- Hecht C, Hook E (1996) Rates of Down syndrome at live birth by one-year maternal age intervals in studies with apparent close to complete ascertainment in populations of European origin: A proposed revised rate schedule for use in genetic and prenatal screening. Am J Med Genet 62: 376-385.
- Hobbs CA, Sherman SL, Yi P, Hopkins SE, Torfs CP, Ne RJ (2000) Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet 67: 623-630.
- James S (2004) Maternal metabolic phenotype and risk of Down syndrome: beyond genetics. Am J Med Genet A 127A: 1-4.
- Kaur A, Kaur A (2013) Prevalence of methylenetetrahydrofolate reductase 677 C-T polymorphism among mothers of Down syndrome children. Indian J Hum Genet 19: 412-414.
- Loughlin SA, Redha A, McIver J, Boyd E, Carothers A, Connor JM (1991) Analysis of the origin of Turner's syndrome using polymorphic DNA probes. J Med Genet 28: 156-158.
- Morton NE, Jacobs PA, Hassold T, Wu D (1988) Maternal age in trisomy. Ann Hum Genet 52: 227-235.
- Neagos D, Cretu R, Sfetea R, Mierla D, Bohiltea L (2012) Investigation of the relationship between the risk of spontaneous abortion and C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene. Revista Română de Medicină de Laborator 20: 335-343.
- Oliveira KC, Bianco B, Verreschi ITN, Guedes AD, Galera BB, Galera MF et al. (2008) Prevalence of the polymorphism MTHFR A1298C and not MTHFR C677T is related to chromosomal aneuploidy in Brazilian Turner Syndrome patients. Arq Bras Endocrinol Metabol 52: 1374-1381.
- Oliveira KC, Verreschi IT, Bianco B, Lipay MV et al. (2012) C677T and A1298C polymorphisms of MTHFR gene and their relation to homocysteine levels in Turner syndrome. Genet Test Mol Biomarkers 16: 396-400.
- Risch N, Stein Z, Kline J, Warburton D (1986) The relationship between maternal age and chromosome size in autosomal trisomy. Am J Hum Genet 39: 68-78.
- Sadiq M, Al-Refai E, Al-Nasser A, Khassawneh M, Al-Batayneh Q (2011) Methylenetetrahydrofolate reductase polymorphisms C677T and A1298C as maternal risk factors for Down syndrome in Jordan. Genet Test Mol Biomarkers 15: 51-7.
- Santos K, Lemos-Marini S, Baptista M, Bonadia L (2006) Frequency of 677C → T and 1298A → C polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene in Turner syndrome individuals. Genetics and Molecular Biology 29: 41-44.
- Shin Young Kim, So Yeon Park, Ji Won Choi, Do Jin Kim, Shin Yeong Lee, Ji Hyae Lim et al. (2011) Association Between MTHFR 1298A>C Polymorphism and Spontaneous Abortion with Fetal Chromosomal Aneuploidy. Am J Reprod Immunol 66: 252-258.
- Song K, Elston RC (2006) A powerful method of combining measures of association and Hardy-Weinberg disequilibrium for fine-mapping in case-control studies. Stat Med 25: 105-126.
- Steed MM, Tyagi SC (2011) Mechanisms of cardiovascular remodeling in hyperhomocysteinemia. Antioxid Redox Signal 15: 1927-1943.
- Stern LL, Mason JB, Selhub J, Choi SW (2000) Genomic DNA hypomethylation, a characteristic in most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol Biomarkers Prev 9: 849-853.
- Stochholm K, Juul S, Juel K (2006) Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 91: 3897-3902.
- Malini SS, Ramachandra NB (2010) Young mothers produce more chromosomal syndrome babies in Mysore, South India. Int J Hum Genet 10: 105-112.
- Verma RS, Babu A (1995) Tissue culture techniques and chromosome preparation. In Human Chromosomes. Principles and Techniques, Verma RS, Babu A, eds. pp 6-71. McGraw-Hill, New York.
- Wang L, Wang D, Zou X, Xu C (2009) Mitochondrial functions on oocytes and preimplantation embryos. J Zhejiang Univ Sci B 10: 483-92.
- Weisberg I, Tran P, Christensen B, Sibani S, Rozen R (1998) A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 64: 169-72.
Publication order reference