The Production of Transgenic Mice Expressing Human Cystathionine Beta-Synthase to Study Down Syndrome

Butler, Christine A.; Knox, Aaron; Bowersox, Jeffrey; Forbes, Stacy; Patterson, David

doi:10.1007/s10519-006-9046-y

Cited by 22 publications

(26 citation statements)

References 34 publications

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“…On the other hand, CBS is a key enzyme in the homocysteine to cystathionine transsulfuration step that plays a critical role in linking the folate and methionine cycles and in regulating homocysteine levels [6]. Recent evidence has demonstrated that CBS 844ins68 has no statistically significant effects on homocysteine and folate concentrations, but it appears to counterbalance the homocysteine-raising and folate-lowering effects of the MTHFR 677TT genotype, making it similar to that observed in MTHFR 677CT or CC individuals [26].…”

Section: Discussionmentioning

confidence: 97%

Investigation of CBS, MTR, RFC-1 and TC Polymorphisms as Maternal Risk Factors for Down Syndrome

et al. 2009

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Abstract. Recent evidence shows that almost 92% of the DS children are born from young mothers, suggesting that other risk factors than advanced maternal age must be involved. In this context, some studies demonstrated a possible link between DS and maternal polymorphisms in genes involved in folate metabolism. These polymorphisms, as well as low intake of folate could generate genomic instability, DNA hypomethylation and abnormal segregation, leading to trisomy 21. We compared the frequency of CBS 844ins68, MTR 2756A>G, RFC-1 80G>A and TC 776C>G polymorphisms among 114 case mothers and 110 matched controls, in order to observe whether these variants act as risk factors for DS. The genotype distributions revealed that there were not significant differences between both samples. However, when we proceed the multiplicative interaction analyses between the four polymorphisms described above together with the previously studied MTHFR 677C>T, MTHFR 1298A>C and MTRR 66A>G polymorphisms, our results show that the combined genotype TC 776CC / MTHFR 677TT and TC 776CC / MTR 2756AG were significantly higher in the control sample. Nevertheless, there was no significant association after Bonferroni correction. Our results suggest that maternal folate-related polymorphisms studied here have no influence on trisomy 21 susceptibility in subjects of Brazilian population.

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Section: Discussionmentioning

confidence: 97%

Investigation of CBS, MTR, RFC-1 and TC Polymorphisms as Maternal Risk Factors for Down Syndrome

et al. 2009

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“…Functional regeneration of this methionine synthase requires the participation of another enzyme, methionine synthase reductase, which is encoded by the MTRR gene [23]. Cystathioninebeta-synthase (CBS) acts in the transulfuration of homocysteine to cystathionine, playing a critical role in linking the folate and methionine cycles in regulating homocysteine levels [9]. Another important protein involved in this metabolism is folate-transporting protein (RFC-1), transporting 5-methyltetrahydrofolateinto the cells [26].…”

Section: Introductionmentioning

confidence: 99%

Maternal Gene Polymorphisms Involved in Folate Metabolism as Risk Factors for Down Syndrome Offspring in Southern Brazil

et al. 2010

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Abstract. This study aimed to investigate the role of maternal polymorphisms, as well as their risk genotypes combinations of MTR A2756G, MTRR A66G, CBS 844ins68, and RFC A80G, involved in folate/homocysteine metabolism, as possible risk factors for Down syndrome (DS) in Southern Brazil. A case-control study was conducted with 239 mothers of DS children and 197 control mothers. The investigation of polymorphisms was performed by PCR and PCR-RFLP. The distribution of genotypic variants was similar in both groups when they were analyzed separately. An investigation of combined risk genotypes showed that the risk of having a DS child for one, two or three risk genotypes was 6.23, 6.96 and 5.84 (95%CI 1.48-26.26; 1.69-28.66; 1.37-24.86), respectively. The combined MTRR 66G and MTHFR 677T alleles were significantly more common among mothers of children with DS than among control mothers (OR 1.55; IC 95% 1.03-2.35). The results show that individual polymorphisms studied in this work are not associated with DS; however, the effects of the combined risk genotypes among MTR, MTRR, CBS and RFC genes are considered maternal risk factors for DS offspring in our population.

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“…Transgenic mice carrying the hRFC gene were produced from FVB mice using this fragment as described previously (Butler et al, 2006). Transgenic mice were genotyped by PCR.…”

Section: Mouse Husbandrymentioning

confidence: 99%

“…To determine the number of integration sites of the transgene and to verify that the hRFC transgene had not integrated into mouse chromosome 10 (the location of the mRFC gene), metaphase spreads were prepared from transgenic mouse spleens and analyzed by FISH as described previously (Butler et al, 2006).…”

Section: Mouse Husbandrymentioning

confidence: 99%

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A humanized mouse model for the reduced folate carrier

Patterson¹,

Graham²,

Cherian³

et al. 2008

Molecular Genetics and Metabolism

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The ubiquitously expressed reduced folate carrier (RFC) or SLC19A1 is recognized to be an essential transport system for folates in mammalian cells and tissues. In addition to its generalized role as a folate transporter, RFC provides specialized tissue functions including absorption across intestinal/ colonic epithelia, transport across the basolateral membrane of renal proximal tubules, transplacental transport of folates, and folate transport across the blood-brain barrier. The human RFC (hRFC) gene is regulated by 5 major upstream non-coding regions (designated A1/A2, A, B, C, and D), each transcribed from a unique promoter. Altogether, at least 14 distinct hRFC transcripts can be envisaged in which different 5' untranslated regions (UTRs) are fused to a common splice acceptor region (positions -1 to -49) within the first coding exon with a common 1776 bp coding sequence. The 5' non-coding regions are characterized by alternate transcription start sites, multiple splice forms, and selective tissue distributions. Alternate 5'UTRs impact mRNA stabilities and translation efficiencies, and result in synthesis of modified hRFC proteins translated from upstream AUGs. In this report, we describe production and characterization of transgenic mice (TghRFC1) containing a functional hRFC gene and of humanized mice in which the mRFC gene is inactivated and an active hRFC gene has been introduced. The mice appear to be healthy and to breed well. Analysis of tissue specificity of expression in both the TghRFC1 and humanized hRFC mice by real-time RT-PCR demonstrates that the hRFC gene is expressed with a specificity closely resembling that seen in human tissues. For the humanized hRFC mice, levels of B and A1/A2 5'UTRs predominated in all mice/tissues, thus resembling results in normal human tissues. Lower levels of A and C 5'UTRs were also detected. The availability of humanized mouse models for hRFC will permit investigators to address critical unanswered questions pertinent to human health and disease. These include the ability to analyze the hRFC gene in vivo, to control dietary and other environmental conditions that may impact levels of gene expression, and to control the genetics of the mice in order to assess the effects of hRFC gene alterations on tissue folate uptake and distribution, none of which can be easily achieved in human populations.

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The Production of Transgenic Mice Expressing Human Cystathionine Beta-Synthase to Study Down Syndrome

Cited by 22 publications

References 34 publications

Investigation of CBS, MTR, RFC-1 and TC Polymorphisms as Maternal Risk Factors for Down Syndrome

Investigation of CBS, MTR, RFC-1 and TC Polymorphisms as Maternal Risk Factors for Down Syndrome

Maternal Gene Polymorphisms Involved in Folate Metabolism as Risk Factors for Down Syndrome Offspring in Southern Brazil

A humanized mouse model for the reduced folate carrier

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