Article

MTHFR New Gene Variants Increase Risk Factor in Wilms' tumor and Prediction of 3D Structure Modulates Functional Activity During Drug -Protein Interaction

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Abstract

Wilms' tumor (WT) is an embryonic tumor of kidney that belongs to paediatric age group. The etiopathology is highly complex due to interaction between genetic and epigenetic factors. The genetic heterogeneity of methylene tetrahydrofolate reductase (MTHFR) gene polymorphism increase "risk factor" of the disease. The present study has been designed to identify new gene variants single nucleotide polymorphism (SNP) of MTHFR using Sanger's sequencing and decode the nucleotide sequences into corresponding amino acids to understand the translational events. Further, allele refractive mutation system with polymerase chain reaction (ARMS-PCR) was also used to confirm mutations (frequency) in the cases of WT and compare with age matched controls. Present findings reveal that genetic heterozygosity was observed in 20% cases of WT by substitution of nucleotide cytosine in to thymidine (C→T) followed by change of amino acid alanine is replaced by valine due to missense mutation. DNA sequencing data varies in different cases of WT that includes-first case shows four new SNPs-1) nucleotide cytosine is substitute by thymidine (C→T) followed by change in amino acid alanine is replaced by valine, 2) thymidine change into adenine (T→A) results in isoleucine→asparagine, 3) cytosine is substitute by adenine (C→A) results in isoleucine →asparagine, and 4) thymidine is substitute by cytosine (T→C), where phenylalanine →serine. Similarly, Second and third case of WT again showing the missense mutation, where the nucleotide cytosine is substitute by thymidine (C→T) followed by alanine→valine and thymidine into adenine (T→A) followed by change in isoleucine→asparagine, respectively. Based on bioinformatics analysis, the 3D structure predicted that the mutation in MTHFR gene modulate the functional activity of ligand binding sites either with protein or methotrexate. Collective findings of PCR and DNA sequencing suggests that these new gene variants which has not been reported earlier might have interfere in folate-metabolism during DNA methylation and increase genetic susceptibility and "risk factor" in WT cases.

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... In human, MTHFR gene is thermolabile in nature and present on chromosome 1p3 6.3. The polymorphic variation of C677T allele (rs1801133) , the missense (point) mutation is responsible for the reduction enzymatic activity (30% -70%) followed by increase "risk factor" in the variety of disease in heterozygous condition other than CHDs, such as neural tube defects (NTD), mental retardation, miscarriage and cancers [12][13][14][15][16][17]. Only few studies have been demonstrated regarding variations of MTHFR allele in CHD cases in Indian population [18,19]. ...
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Wilms tumor is genetically heterogeneous, and until recently only one Wilms tumor gene was known, WT1 at 11p13. However, WT1 is altered in only approximately 20% of Wilms tumors. Recently a novel gene, WTX at Xq11.1, was reported to be mutated in Wilms tumors. No overlap between tumors with mutations in WTX and WT1 was noted, suggesting that WT1 and WTX mutations could account for the genetic basis of roughly half of Wilms tumors. To assess the frequency of WTX mutations and their relationship to WT1 mutations in a larger (n = 125) panel of Wilms tumors which had been thoroughly assessed for mutations in WT1, we conducted a complete mutational analysis of WTX that included sequencing of the entire coding region and quantitative PCR to identify deletions of the WTX gene. Twenty-three (18.4%) tumors carried a total of 24 WTX mutations, a lower WTX mutation frequency than that previously observed. Surprisingly, we observed an equivalent frequency of WTX mutations in tumors with mutations in either or both WT1 and CTNNB1 (20.0%) and tumors with no mutation in either WT1 or CTNNB1 (17.5%). WTX has been reported to play a role in the WNT/beta-catenin signaling pathway, and, interestingly, WTX deletion/truncation mutations appeared to be rare in tumors carrying exon 3 mutations of CTNNB1, encoding beta-catenin. Our findings indicate that WT1 and WTX mutations occur with similar frequency, that they partially overlap in Wilms tumors, and that mutations in WT1, WTX, and CTNNB1 underlie the genetic basis of about one-third of Wilms tumors.
Stop Codons of TGF βRI Gene Modulate the Functional Activity of 3D Structure and their Genetic Susceptibility in the Case of Wilms' Tumour
  • A K Saxena
  • V Singh
  • Aprajita
Saxena AK, Singh V, Aprajita, et al. Stop Codons of TGF βRI Gene Modulate the Functional Activity of 3D Structure and their Genetic Susceptibility in the Case of Wilms' Tumour. J Cancer Sci Ther 11 (2019): 251-255.
Penetrance of WT1 and WT2 Gene Mutation and Loss of Heterozygosity in Wilms tumors in Indian Population
  • A K Saxena
  • V Singh
  • V Kumar
Saxena AK, Singh V, Kumar V et al. Penetrance of WT1 and WT2 Gene Mutation and Loss of Heterozygosity in Wilms tumors in Indian Population. Int J Cancer Res Ther 5 (2020): 3-1
FISH analysis for Drug and Chemical Mediated Cellular Toxicity. SpringerBriefs in Applied Sciences and Technology
  • A K Saxena
  • A Kumar
Saxena AK, Kumar A. FISH analysis for Drug and Chemical Mediated Cellular Toxicity. SpringerBriefs in Applied Sciences and Technology. Springer Nature Singapore. Pte Ltd (2020): 43-57.
MTHFR New Gene Variants Increase Risk Factor in Wilms'tumor and Prediction of 3D Structure Modulates Functional Activity During Drug -Protein Interaction
  • Ajit Saxena
  • Vijayendra Kumar
  • Aniket Kumar
  • Chandan Kumar Kumar
  • Singh
How to cite this article: Saxena, Ajit Kumar, Vijayendra Kumar, Aniket Kumar, Chandan Kumar Singh. "MTHFR New Gene Variants Increase Risk Factor in Wilms'tumor and Prediction of 3D Structure Modulates Functional Activity During Drug -Protein Interaction" J Integr Oncol 9(2020):** doi: 10.37421/jio.2020.9.3.355