Summary
Down syndrome (trisomy of chromosome 21) (DS) is the most common genetic cause of mental retardation. In our study we employed immunoblotting to evaluate protein expression of reduced folate carrier (hRFC), encoded by a gene localised on chromosome 21, in fetal DS brain. We observed increased expression of hRFC-immunoreactive band with an apparent MW of approximately 150kDa, whereas the other bands (MWs ∼60 and 50kDa), were comparable to control. In conclusion, we suggest that aberrant hRFC expression may well have a role in the already observed deterioration of folate metabolism in DS. Moreover, no alterations of expression level of p53 and Sp1, supposed to play a role in the regulation of hRFC, suggest that regulation of hRFC expression in fetal life by these proteins is highly unlikely, at least by changes in their protein level.
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References
Al-Gazali L, Padmanabhan R, Melnyk S, Yi P, Pogribny IP, Bakir M, Hamid ZA, Abdulrazzaq Y, Dawodu A, James SJ (2001) Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neuroal tube defect. Am J Med Genet 103: 128–132
Bailey LB, Gregory JF 3rd (1999) Folate metabolism and requirements. J Nutr 129: 779–782
Black AR, Black JD, Azizkhan-Clifford J (2001) Spl and Krüpepel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol 188: 143–160
Borellini F, Glazer RI (1993) Induction of Spl-p53 DNA-binding heterocomplexes during granulocyte/macrophage colony-stimulating factor-dependent proliferation in human erythroleukemia cell line TF-1. J Biol Chem 268: 7923–7928
Bottiglieri T (1996) Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev 54: 382–390
Brodsky G, Barnes T, Bleskan J, Becker L, Cox M, Patterson D (1997) The human GARS-AIRS-GART gene encodes two proteins which are differentially expressed during human brain development and temporally overexpressed in cerebellum of individuals with Down syndrome. Hum Mol Genet 6: 2043–2050
Chadefaux B, Rethore MO, Raoul O, Ceballos I, Poissonnier M, Gilgenkranz S, Allard D (1985) Cystathione beta synthase: gene dosage effect in trisomy 21. Biochem Biophys Res Commun 128: 40–44
Cheon MS, Bajo M, Kim SH, Claudio JO, Patterson D, Kruger WD, Kondoh H, Lubec G (2003) Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: challenging the gene dosage effect hypothesis, part II. Amino Acids 24: 119125
Ding BC, Whetstine JR, Witt TL, Schuetz JD, Matherly LH (2001) Repression of human reduced folate carrier gene expression by wild type p53. J Biol Chem 276: 8713–8719
Epstein CJ (2001) Down syndrome (trisomy 21). In: Scriver SR, Beaudet AL, Sly WS,Valle D (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 1223–1256
Erbe RW (1975) Inborn errors of folate metabolism, part II. N Engl J Med 293: 807–812
Hobbs CA, Sherman SL, Yi P, Hopkins SE, Torfs CP, Hine RJ, Pogribna M, Rozen R, James SJ (2000) Polymorphism in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet 67: 623–630
Kruman II, Culmsee C, Chan SL, Kruman Y, Guo Z, Penix L, Mattson MP (2000) Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 20: 6920–6926
Lipton SA, Kim WK, Choi YB, Kumar S, D’Emilia DM, Raydu PV, Arnelle DR, Stamler JS (1997) Neurotoxicity associated with dual actions of homocysteine at the Nmethyl-D-aspartate receptor. Proc Natl Acad Sci USA 94: 5923–5928
Martin DC (1988) B12 and folate deficiency demencia. Clin Geriatr Med 4: 841–852
Matherly LH (2001) Molecular and cellular biology of the human reduced folate carrier. Prog Nucl Acid Res Mol Biol 67: 131–162
Naggar H, Ola MS, Moore P, Huang W, Bridges CC, Ganapathy V, Smith SB (2002) Downregulation of reduced-folate transporter by glucose in cultured RPE cells and in RPE of diabetic mice. Invest Ophtalmol Vis Sci 43: 556–563
Pogribna M, Melnyk S, Pogribny IP, Chango A, Yi P, James SJ (2001) Homocysteine metabolism in children with Down syndrome: in vitro modulation. Am J Hum Genet 69: 88–95
Scholl TO, Johnson WG (2000) Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr 71: 1295S - 1303S
Seidl R, Fang-Kircher S, Bidmon B, Cairns N, Lubec G (1999) Apoptosis-associated proteins p53 and APO-1/Fas (CD95) in brains of adult patients with Down syndrome. Neurosci Lett 260: 9–12
Sirotnak FM, Tolner B (1999) Carrier-mediated membrane transport of folates in mammalian cells. Annu Rev Nutr 19: 91–122
Snowdon DA, Tully CL, Smith CD, Riley KP, Markesbery WR (2000) Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun Study. Am J Clin Nutr 71: 993–998
Tolner B, Roy K, Sirotnak FM (1998) Structural analysis of the human RFC-1 gene encoding a folate transporter reveals multiple promoters and alternatively spliced transcripts with 5’end heterogeneity. Gene 211: 331–341
Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L (2001) Vitamin B(12) and folate in relation to the development of Alzheimer’s disease. Neurology 56: 1188–1194
Wang Q, Beck WT (1998) Transcriptional suppression of multidrug resistence-associated protein (MRP) gene expression by wild-type p53. Cancer Res 58: 5762–5769
Wang Y, Zhao R, Russell RG, Goldman ID (2001) Localization of the murine reduced folate carrier as assed by immunohistochemical analysis. Biochim Biophys Acta 1513: 49–54
Whetstine JR, Matherly LH (2001) The basal promoters for the human reduced folate carrier gene are regulated by a GC-box and a cAMP-response element/AP-1-like element. Basis for tissue-specific gene expression. J Biol Chem 276: 6350–6358
Wong SC, Zhang L, Proefke SA, Matherly LH (1998) Effects of the loss of capacity for N-glycosylation on the transport activity and cellular localization of the human reduced folate carrier. Biochim Biophys Acta 1375: 6–12
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Lubec, G., Bajo, M., Cheon, M.S., Bajova, H., Matherly, L.H. (2003). Increased expression of human reduced folate carrier in fetal Down syndrome brain. In: Lubec, G. (eds) Advances in Down Syndrome Research. Journal of Neural Transmission Supplement 67, vol 67. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6721-2_8
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DOI: https://doi.org/10.1007/978-3-7091-6721-2_8
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