Saadet ARSAN, Gülhis DEDA, Mesiha EKİM, Nejat AKAR, Ece AKAR, Yonca EĞİN

Neural Tube Defects and 19 bp Deletion Within Intron-1 of Dihydrofolate Reductase Gene

Aims: Dihydrofolate reductase (DHFR) is necessary for the reduction of the ingested folates before they are used in the body metabolism. Thus, the DHFR enzyme has an important role in folate supplementation and the DHFR gene is a strong candidate for a teratogenic locus for neural tube defects (NTDs). There is a 19 bp deletion within the first intron of the DHFR gene, which may have an effect on folate reduction. We thus studied this mutation in Turkish spina bifida patients and their mothers to determine whether there is an association with the occurrence of NTD. Materials and Methods: The case-control study included 69 meningomyelocele (MMC) patients and 104 mothers who gave birth to NTD babies. One hundred sixty eight women, consecutively selected, who admitted to the laboratory, were included as controls. One hundred thirty-six newborns without MMC were also included. Results: DHFR gene 19 bp deletion in homozygous state was significantly higher in the MMC group compared to control newborns [Odds Ratio 2.4 (CI 95% 0.95-6.08)]. It also brought 2.4- fold risk [Odds Ratio 2.4 (CI 95% 1.04-5.6)] in NTD mothers compared to controls. Conclusions: Our data revealed that DHFR gene 19 bp deletion homozygosity and other possible mutations in the DHFR gene should be studied further especially in folate-supplemented mothers with NTD recurrence.

Anahtar Kelimeler:

Neural tube defects, spina bifida, dihydrofolate reductase

Neural Tube Defects and 19 bp Deletion Within Intron-1 of Dihydrofolate Reductase Gene

Keywords:

Neural tube defects, spina bifida, dihydrofolate reductase,

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Campbell LR, Dayton DH, Sohal GS. Neural tube defects: a review of human and animal studies on the etiology of neural tube defects. Teratology 1986; 34: 171-8.
Akar N, Çavdar AO, Arcasoy A. High incidence of neural tube defect in Bursa, Turkey. Paediatric Perinat Epid 1988; 2: 89-92.
MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338: 131-7.
Akar N, Akar E, Deda G, Arsan S. Spina bifida and common mutations at the homocysteine metabolism pathway. Clin Genet 2000; 57: 230-1.
Boduroglu K, Alikasifoglu M, Anar B, Tuncbilek E. 677 CT mutation on the methylenetetrahydrofolate reductase gene is not a risk factor for neural tube defects in Turkey. Arch Dis Child 1998; 78: 235. 6. Steegers-Theunissen RPM, Boers GHJ, Trijbels FJJM, Finkelstein JJD, Blom HJ, Thomas CMG. Maternal hyperhomocysteinemia: a risk factor for neural-tube defects? Metabolism 1994; 43: 1475- 80.
Smithells RW, Sheppard S. Possible prevention of neural tube defects by periconceptional vitamin supplementation. Lancet 1980; 1: 647. 8. Wild J, Read AP, Sheppard S, Seller MJ, Smithells RW, Nevin NC. Recurrent neural tube defects, risk factors and vitamins. Archs Dis Child 1986; 61: 440-4.
Anderson AC. Targeting DHFR in parasitic protozoa. Drug
Discovery Today 2005; 10(2): 121-8.
Johnson WG, Stenroos ES, Spychala JR, Chatkupt S, Ming SX, Buyske S. New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR): a risk factor for spina bifida acting in mothers during pregnancy? Am J Med Genet 2004; 124A(4): 339-45.
Van der Linden IJ, Nguyen U, Heil SG, Franke B, Vloet S, Gellekink H et al. Variation and expression of dihydrofolate reductase in relation to spina bifida. Mol Genet Metab 2007; 91(1): 98-103.
Parle-McDermott A, Pangilinan F, Mills JL, Kirke PN, Gibney ER, Troendle J. The 19-bp deletion polymorphism in intron-1 of dihydrofolate reductase may decrease rather than increase risk for spina bifida in the Irish population. Am J Med Genet A 2007; 143(11): 1174-80.