Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2009. / Härtill 4 uppsatser.

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The relationship between colorectal cancer (CRC) and folate metabolism is complex. Dietary folate, depending on the timing and dose, may either prevent or enhance tumour initiation and/or growth, and polymorphisms in the genes encoding folate-metabolising enzymes may also modulate risk. In this thesis, the Apcmin/+ mouse model of CRC was used to investigate the effect of nutritional and genetic disturbances in folate metabolism on tumourigenesis and to examine various mechanisms. / The reduced folate carrier I (RFC1) is responsible for the cellular uptake and intestinal absorption of folate, primarily the 5-methyltetrahydrofolate (5-methylTHF) derivative. Methionine synthase (MTR) uses 5-methylTHF to remethylate homocysteine to methionine, which may be activated and used to methylate substrates such as DNA. 5-MethylTHF is also the product of the methylenetetrahydrofolate reductase (MTHFR)-catalysed reduction of 5,10-methyleneTHF, which is also used to convert dUMP to dTMP. / Adenoma number and load were reduced in Rfc1+/-Apc min/+ mice, compared with Rfc1+/+Apc min/+ mice, but were similar in Mtr+/-Apc min/+ and Mtr+/+ Apcmin/+ mice. Neither Rfc1 nor Mtr genotype affected global DNA methylation, apoptosis or plasma homocysteine (tHcy) levels. In the experiments involving Mtr mice, dietary folate deficiency increased adenoma number, plasma tHcy, and apoptosis, and decreased global DNA methylation. Neither Mtr nor Rfc1 genotype affected the dUTP/dTTP ratio in the intestine of mice not predisposed to adenoma formation. / Adenoma number was decreased in Mthfr+/-Apc min/+ mice (compared with Mthfr+/+Apc min/+ mice) and in Mthfr+/+Apc min/+ offspring of Mthfr+/- mothers (compared with Mthfr+/+Apcmin/+ offspring of Mthfr+/+ mothers). A folate-deficient diet, when initiated prior to conception, significantly decreased adenoma number and decreased global DNA methylation. Overall, adenoma number was inversely correlated with plasma tHcy, dUTP/dTTP ratio and apoptosis. When initiated at three weeks of age, a folate-enriched diet significantly increased adenoma number in Apcmin/+ mice. In the intestines of mice not predisposed to adenoma formation, Mthfr deficiency decreased, and folic acid deficiency increased, the dUTP/dTTP ratio. / These results support the evidence that MTHFR polymorphisms are protective in CRC tumourigenesis and that depending on stage or predisposition, folate may inhibit or enhance tumour growth.

Glutamate formiminotransferase deficiency (OMIM 229100) is an autosomal recessive disorder marked by clinical heterogeneity. The severe phenotype, first identified in patients of Japanese descent, includes high levels of formiminoglutamate (FIGLU) in the urine in response to histidine loading, megaloblastic anemia, and mental retardation. The mild phenotype is marked by high levels of FIGLU in the urine in the absence of histidine loading, mild developmental delay and no hematological abnormalities. The gene for human glutamate formiminotransferase-cyclodeaminase consists of 15 exons and is located at 21q22.3. The protein consists of a tetramer of dimers, with dimerization essential for both formiminotransferase and cyclodeaminase activity. / Genomic DNA extracted from cell lines from three patients with suspected glutamate formiminotransferase deficiency was analyzed by PCR and sequencing of individual exons. Cell lines WG 1758 and WG 1759 are from two siblings of Germanic descent. Both siblings are heterozygous for the mutations c457 C → T and c940 G → C. The c457 C → T changes a conserved arginine to a cysteine in a loop involved in the binding of formiminotetrahydrofolate to the enzyme. The c940 G → C mutation converts an arginine to a proline in an alpha-helix essential for the dimerization of the formiminotransferase domain. Cell line WG 1795 is from a patient of Danish descent. The patient appears to be hemizygous for a c1033 insG mutation. Quantitative PCR suggests the presence of a deletion on the other chromosome, which minimally encompasses exon 9. All of the FTCD gene changes were absent in 100 control individuals (200 alleles).

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Folate deficiency, a prevalent vitamin deficiency in America, can stem from environmental and/or genetic causes. The most common inborn error of folate metabolism is deficiency of methylenetetrahydrofolate reductase (MTHFR), which catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Severe MTHFR deficiency results in hyperhomocysteinemia and homocystinuria; patients present with developmental delay, and various neurological and vascular disorders. This thesis describes three mutations identified in the MTHFR locus in patients with severe deficiency: 1025T→C (M→T), 1027T→G (W→G), and 1768G→A (E→K). Genotype-phenotype correlations are described, along with biochemical characterization of three mutations (983A→G (N→S), 1025T→C, 1027T→G). All three mutations exert their effect by decreasing Vmax without changing the enzyme's affinity for its substrate, 5-methyltetrahydrofolate. The 983A→G variant also conferred decreased affinity for FAD, a cofactor. / The more common and mild deficiency observed in the general healthy population is probably due in part to insufficient dietary intake of folate. Folate deficiency has been associated with increased risk for colon cancer. In a pilot study presented here, the impact of altered folate intake on tumor multiplicity in the Min mouse, a model for multiple intestinal neoplasia, was assessed. Folate deficient diets did not produce a consistent change in tumor numbers. However, a linear correlation between S-adenosylmethionine and S-adenosylhomocysteine content of preneoplastic tissue and tumor multiplicity was identified. / This thesis contributes to our understanding of the impact of genetic- and/or dietary-induced folate deficiency on cellular and organismal functions.

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