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A folate receptor alpha double-mutated haplotype 1816delC-1841A is distributed throughout Eurasia and associated with lower erythrocyte folate levels.
Mol Biol Rep. 2012 Apr; 39(4):4471-8.MB

Abstract

Folate is crucial for various cellular functions. Several transport mechanisms allow folate to enter the intracellular compartment with folate receptor-α being the major high-affinity receptor. Rare genetic variations in exons of the FR-α gene, FOLR1, were recently shown to cause severe folate deficiency accompanied by neurological and other disturbances. So far, similar effects by genetic variation in noncoding parts of the FOLR1 gene have not been identified. The aim of our study was to determine biochemically the haplotype structure of two linked polymorphisms in the FOLR1 gene, 1816delC and 1841G>A, the prevalences of the mutated alleles across Eurasia, and their possible effects on physiological folate levels in vivo. For this purpose we employed allele-specific PCR and Pyrosequencing technology and performed genotyping in 738 subjects from Spain, 387 from Sweden, 952 from Estonia, and 47 from Korea. We demonstrate the presence of an ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, with the prevalence of the mutated allele being highest among Koreans (q = 0.074), lower in Estonians (q = 0.017), Spaniards (q = 0.0061), and the lowest among Swedes (q = 0.0026). Erythrocyte folate levels were studied in the Spanish population sample, where subjects carrying the double-mutated FOLR1 haplotype had significantly reduced levels by 27% (P = 0.039), adjusted for serum vitamin B(12) levels and MTHFR 677C>T genotype, while the mean serum folate levels were only 20% lower among the carriers (P = 0.11). Plasma homocysteine and cobalamin levels did not differ. Thus, we have demonstrated by molecular haplotyping an ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, spread over the whole Eurasian continent, which may be of functional importance for uptake of folate in red blood cells.

Authors+Show Affiliations

Department of Laboratory Medicine, Clinical Chemistry, Örebro University Hospital, and School of Health and Medical Sciences, Örebro University, 701 85, Örebro, Sweden. torbjorn.nilsson@orebroll.seNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21938430

Citation

Nilsson, Torbjörn K., et al. "A Folate Receptor Alpha Double-mutated Haplotype 1816delC-1841A Is Distributed Throughout Eurasia and Associated With Lower Erythrocyte Folate Levels." Molecular Biology Reports, vol. 39, no. 4, 2012, pp. 4471-8.
Nilsson TK, Laanpere M, Altmäe S, et al. A folate receptor alpha double-mutated haplotype 1816delC-1841A is distributed throughout Eurasia and associated with lower erythrocyte folate levels. Mol Biol Rep. 2012;39(4):4471-8.
Nilsson, T. K., Laanpere, M., Altmäe, S., Serra-Majem, L., & Salumets, A. (2012). A folate receptor alpha double-mutated haplotype 1816delC-1841A is distributed throughout Eurasia and associated with lower erythrocyte folate levels. Molecular Biology Reports, 39(4), 4471-8. https://doi.org/10.1007/s11033-011-1236-x
Nilsson TK, et al. A Folate Receptor Alpha Double-mutated Haplotype 1816delC-1841A Is Distributed Throughout Eurasia and Associated With Lower Erythrocyte Folate Levels. Mol Biol Rep. 2012;39(4):4471-8. PubMed PMID: 21938430.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A folate receptor alpha double-mutated haplotype 1816delC-1841A is distributed throughout Eurasia and associated with lower erythrocyte folate levels. AU - Nilsson,Torbjörn K, AU - Laanpere,Margit, AU - Altmäe,Signe, AU - Serra-Majem,Lluís, AU - Salumets,Andres, Y1 - 2011/09/22/ PY - 2010/11/08/received PY - 2011/09/13/accepted PY - 2011/9/23/entrez PY - 2011/9/23/pubmed PY - 2012/6/29/medline SP - 4471 EP - 8 JF - Molecular biology reports JO - Mol Biol Rep VL - 39 IS - 4 N2 - Folate is crucial for various cellular functions. Several transport mechanisms allow folate to enter the intracellular compartment with folate receptor-α being the major high-affinity receptor. Rare genetic variations in exons of the FR-α gene, FOLR1, were recently shown to cause severe folate deficiency accompanied by neurological and other disturbances. So far, similar effects by genetic variation in noncoding parts of the FOLR1 gene have not been identified. The aim of our study was to determine biochemically the haplotype structure of two linked polymorphisms in the FOLR1 gene, 1816delC and 1841G>A, the prevalences of the mutated alleles across Eurasia, and their possible effects on physiological folate levels in vivo. For this purpose we employed allele-specific PCR and Pyrosequencing technology and performed genotyping in 738 subjects from Spain, 387 from Sweden, 952 from Estonia, and 47 from Korea. We demonstrate the presence of an ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, with the prevalence of the mutated allele being highest among Koreans (q = 0.074), lower in Estonians (q = 0.017), Spaniards (q = 0.0061), and the lowest among Swedes (q = 0.0026). Erythrocyte folate levels were studied in the Spanish population sample, where subjects carrying the double-mutated FOLR1 haplotype had significantly reduced levels by 27% (P = 0.039), adjusted for serum vitamin B(12) levels and MTHFR 677C>T genotype, while the mean serum folate levels were only 20% lower among the carriers (P = 0.11). Plasma homocysteine and cobalamin levels did not differ. Thus, we have demonstrated by molecular haplotyping an ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, spread over the whole Eurasian continent, which may be of functional importance for uptake of folate in red blood cells. SN - 1573-4978 UR - https://www.unboundmedicine.com/medline/citation/21938430/full_citation/A_folate_receptor_alpha_double_mutated_haplotype_1816delC_1841A_is_distributed_throughout_Eurasia_and_associated_with_lower_erythrocyte_folate_levels_ L2 - https://doi.org/10.1007/s11033-011-1236-x DB - PRIME DP - Unbound Medicine ER -