Methylenetetrahydrofolate reductase mutations, a genetic cause for familial recurrent neural tube defects

Yaliwal, Laxmi V; Desai, Rathnamala M

doi:10.4103/0971-6866.96680

Cited by 17 publications

(19 citation statements)

References 5 publications

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“…MTHFR enzyme deficiency was calculated by adding up the total loss of enzymatic functions from both MTHFR C677T and A1298C polymorphisms, 35% for 677 CT and 70% for 677 TT polymorphisms, and 15% for 1298 AC and 30% for 1298 CC variants [ 20 , 21 , 58 ]. The total gene mutations from five genes were computed together, with possible ranges of 0–10, with scores of one for heterozygous and two for homozygous polymorphism mutations per each of the five genes included in this study.…”

Section: Methodsmentioning

confidence: 99%

“…We examined two loci of MTHFR gene polymorphisms, C677T (rs1801133) and A1298C (rs1801131), both are associated with MTHFR enzymatic deficiency resulting in increased homocysteine concentrations [ 18 , 19 ]. The best-characterized MTHFR gene polymorphism is a common missense/loss of function mutation of 677C→T, resulting in a thermolabile enzyme variant that has a reduced catalytic activity of 35% for 677 CT and 70% for 677 TT variants, and of nucleotide 1298A→C, resulting in 15% decreased MTHFR activity for 1298 AC and 30% for 1298 CC variants [ 20 , 21 ]. We also investigated three additional genes in the folate-methylation pathways: dihydrofolate reductase ( DHFR ) 19 base pair ( 19bp ) (rs70991108) which converts folic acid into methylenetetrahydrofolate (MTHF) as usable folate form [ 22 , 23 ], methionine synthase ( MTR A2756G, rs1805087) in the methylation cycle, and methionine synthase reductase ( MTRR A66G, rs1801394) which converts/recycles homocysteine back to usable MTR for the methylation cycle [ 24 , 25 , 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…Together, these five genes play critical roles in the methylation pathways for biological processes in sustaining human health, and polymorphism mutations of these genes would lead to missense and lost functions for the methylation process. Sufficient nutrients related to these genes include folate (vitamin B9) and vitamin B12, as methyl donors, play an integral role in the phenotypic expression of MTHFR and related gene mutations in the methylation pathways [ 18 , 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Gene Environment Interactions and Predictors of Colorectal Cancer in Family-Based, Multi-Ethnic Groups

Shiao

Grayson

et al. 2018

JPM

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For the personalization of polygenic/omics-based health care, the purpose of this study was to examine the gene–environment interactions and predictors of colorectal cancer (CRC) by including five key genes in the one-carbon metabolism pathways. In this proof-of-concept study, we included a total of 54 families and 108 participants, 54 CRC cases and 54 matched family friends representing four major racial ethnic groups in southern California (White, Asian, Hispanics, and Black). We used three phases of data analytics, including exploratory, family-based analyses adjusting for the dependence within the family for sharing genetic heritage, the ensemble method, and generalized regression models for predictive modeling with a machine learning validation procedure to validate the results for enhanced prediction and reproducibility. The results revealed that despite the family members sharing genetic heritage, the CRC group had greater combined gene polymorphism rates than the family controls (p < 0.05), on MTHFR C677T, MTR A2756G, MTRR A66G, and DHFR 19 bp except MTHFR A1298C. Four racial groups presented different polymorphism rates for four genes (all p < 0.05) except MTHFR A1298C. Following the ensemble method, the most influential factors were identified, and the best predictive models were generated by using the generalized regression models, with Akaike’s information criterion and leave-one-out cross validation methods. Body mass index (BMI) and gender were consistent predictors of CRC for both models when individual genes versus total polymorphism counts were used, and alcohol use was interactive with BMI status. Body mass index status was also interactive with both gender and MTHFR C677T gene polymorphism, and the exposure to environmental pollutants was an additional predictor. These results point to the important roles of environmental and modifiable factors in relation to gene–environment interactions in the prevention of CRC.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gene Environment Interactions and Predictors of Colorectal Cancer in Family-Based, Multi-Ethnic Groups

Shiao

Grayson

et al. 2018

JPM

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“…Thus, the identification of the rs1801133 genotype is necessary not only for the study of this SNP involving in human diseases but also for the prognosis of treatment with anti-cancer drugs as well as identification of molecular causes of some human diseases. Another application of rs1801133 genotyping is the prediction of the risk of neonatal illness [13]. In fact, there are many molecular protocols/commercial kits for genotyping rs1801133.…”

Section: Introduction Ethylenetetrahydrofolate Reductase (Mthfr)mentioning

confidence: 99%

Building a molecular typing protocol for rs1801133 based on real-time PCR HRM technique

Tran¹,

Nguyen²,

Le³

et al. 2019

Sci. Tech. Dev. J. - Nat. Sci.

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rs1801133 is a single nucleotide polymorphism (SNP) located in the sequence of MTHFR on human chromosome 1. The alleles of this SNP affect the activity of the MTHFR enzyme. People bearing C/T genotype have 66% activity of MTHFR while people with T/T genotype have only 25% activity. These reduced activities of MTHFR cause homocysteinemia. There are several publications on the relationship between homocysteinemia and human diseases such as cardiovascular disease, neurological diseases, abnormal fetus, infertility and cancer. In this study, we built a molecular protocol for genotyping rs1801133 using real-time PCR HRM technique. This protocol could be used for diagnosis of molecular mechanism of homocysteinemia causing the mentoned above diseases as well as for the study of the relationship between rs1801133 and other human diseases. We successfully designed the primer pairs for genotyping and nucleotide sequencing rs1801133 by real-time PCR HRM and Sanger sequencing method. We also examined the optimal MgCl2 concentration for clear differentiation of three rs1801133 genotypes. Performance characteristics of the real-time PCR HRM protocol included of specificity, repeatability, reproducibility was evaluated and it showed good results. Comparison of genotyping results of rs1801133 between the realtime PCR HRM method and the Sanger nucleotide sequencing method showed good concordances. Finally, this real-time PCR HRM protocol for rs1801133 genotyping was applied on 100 human DNA samples to evaluate the clinical utility of the protocol.

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“…Key methyl-donors related to these genes include folate (vitamin B9) and vitamin B12, that play an integral role in the phenotypic expression of MTHFR and related gene mutations in the OCM methylation pathways [ 33 , 34 , 35 , 36 ]. The methyl-donors could compensate for the deficient enzyme-metabolites in the methylation pathways resulted from the loss-of-function gene mutations in the OCM pathway.…”

Section: Introductionmentioning

confidence: 99%

Gene-Metabolite Interaction in the One Carbon Metabolism Pathway: Predictors of Colorectal Cancer in Multi-Ethnic Families

Shiao

Grayson

2018

JPM

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For personalized healthcare, the purpose of this study was to examine the key genes and metabolites in the one-carbon metabolism (OCM) pathway and their interactions as predictors of colorectal cancer (CRC) in multi-ethnic families. In this proof-of-concept study, we included a total of 30 participants, 15 CRC cases and 15 matched family/friends representing major ethnic groups in southern California. Analytics based on supervised machine learning were applied, with the target variable being specified as cancer, including the ensemble method and generalized regression (GR) prediction. Elastic Net with Akaike’s Information Criterion with correction (AICc) and Leave-One-Out cross validation GR methods were used to validate the results for enhanced optimality, prediction, and reproducibility. The results revealed that despite some family members sharing genetic heritage, the CRC group had greater combined gene polymorphism-mutations than the family controls (p < 0.1) for five genes including MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G, and DHFR 19bp. Blood metabolites including homocysteine (7 µmol/L), methyl-folate (40 nmol/L) with total gene mutations (≥4); age (51 years) and vegetable intake (2 cups), and interactions of gene mutations and methylmalonic acid (MMA) (400 nmol/L) were significant predictors (all p < 0.0001) using the AICc. The results were validated by a 3% misclassification rate, AICc of 26, and >99% area under the receiver operating characteristic curve. These results point to the important roles of blood metabolites as potential markers in the prevention of CRC. Future intervention studies can be designed to target the ways to mitigate the enzyme-metabolite deficiencies in the OCM pathway to prevent cancer.

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Methylenetetrahydrofolate reductase mutations, a genetic cause for familial recurrent neural tube defects

Cited by 17 publications

References 5 publications

Gene Environment Interactions and Predictors of Colorectal Cancer in Family-Based, Multi-Ethnic Groups

Gene Environment Interactions and Predictors of Colorectal Cancer in Family-Based, Multi-Ethnic Groups

Building a molecular typing protocol for rs1801133 based on real-time PCR HRM technique

Gene-Metabolite Interaction in the One Carbon Metabolism Pathway: Predictors of Colorectal Cancer in Multi-Ethnic Families

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