MTRR gene variant rs1801394 found in Malaysian patients with neural tube defects
DOI:
https://doi.org/10.31117/neuroscirn.v3i1.41Keywords:
Neural tube defects, MTRR, gene polymorphism, rs1801394, MalaysianAbstract
Neural tube defects (NTDs) are congenital anomalies resulting from the failure of neural tube closure during embryogenesis. The precise molecular mechanisms underlying this multifactorial disease is poorly understood, although single nucleotide polymorphisms in genes involved in the one-carbon metabolism cycle are believed to contribute towards NTD development. Among them is 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Protein function prediction algorithms (PolyPhen-2, PROVEAN, SIFT, SMART-Ensembl) were employed to evaluate its pathogenicity potential caused by the replacement of isoleucine with methionine. Seven NTD patients and 12 of their parents were recruited for this study. DNA samples were collected through blood or saliva whereby the extracted DNAs were then sent for whole exome sequencing (WES). Zygosity of the variant was confirmed from WES data of each subject and further validated through polymerase chain reaction (PCR) and Sanger sequencing. The results revealed that 57% of patients and 83% of parents carried rs1801394 mutation in their MTRR gene, based on either homozygous (G/G) or heterozygous (A/G) genotypes. Bioinformatics analysis of this missense mutation predicted that this change is damaging to MTRR protein function by 2 of the 3 predictor algorithms and that the change from isoleucine to methionine amino acid affects flavodoxin domain of the protein. This impacts enzyme activity within the one-carbon metabolism pathway, which is linked to the aetiology of NTDs. From population databases, this variant was considered common with a MAF >0.3, however, it was not found in the Singapore Genome Variation Project (SGVP), whose population is a closer representation of the Malaysian subjects investigated here. Hence, we explored the prevalence of this variant in other studies and found that its association with NTDs differed across populations worldwide. Finally, we conclude that rs1801394 may be an NTD risk factor in the Malaysian population and should be further investigated as a potential prenatal screening tool.
References
Amorim, M. R., Lima, M. A. C., Castilla, E. E., & Orioli, I. M. (2007). Non-Latin European descent could be a requirement for association of NTDs andMTHFR variant 677C > T: A meta-analysis. American Journal of Medical Genetics Part A, 143A(15), 1726-1732. https://doi.org/10.1002/ajmg.a.31812
Blencowe, H., Cousens, S., Modell, B., & Lawn, J. (2010). Folic acid to reduce neonatal mortality from neural tube disorders. International Journal of Epidemiology, 39 Suppl 1(Suppl 1), i110-21. https://doi.org/10.1093/ije/dyq028
Bomba, L., Walter, K., & Soranzo, N. (2017). The impact of rare and low-frequency genetic variants in common disease. Genome Biology, 18(1), 77. https://doi.org/10.1186/s13059-017-1212-4
Brouns, R., Ursem, N., Lindemans, J., Hop, W., Pluijm, S., Steegers, E., & Steegers-Theunissen, R. (2008). Polymorphisms in genes related to folate and cobalamin metabolism and the associations with complex birth defects. Prenatal Diagnosis, 28(6), 485-493. https://doi.org/10.1002/pd.2006
Chen, H., Hendricks, A. E., Cheng, Y., Cupples, A. L., Dupuis, J., & Liu, C.-T. (2011). Comparison of statistical approaches to rare variant analysis for quantitative traits. BMC Proceedings, 5 Suppl 9(Suppl 9), S113. https://doi.org/10.1186/1753-6561-5-S9-S113
Copp, A. J., Adzick, N. S., Chitty, L. S., Fletcher, J. M., Holmbeck, G. N., & Shaw, G. M. (2015). Spina bifida. Nature Reviews Disease Primers, 1(1), 15007. https://doi.org/10.1038/nrdp.2015.7
Copp, A. J., Stanier, P., & Greene, N. D. E. (2013). Neural tube defects: Recent advances, unsolved questions, and controversies. In The Lancet Neurology (Vol. 12, Issue 8, pp. 799-810). https://doi.org/10.1016/S1474-4422(13)70110-8
Dakal, T. C., Kala, D., Dhiman, G., Yadav, V., Krokhotin, A., & Dokholyan, N. V. (2017). Predicting the functional consequences of non-synonymous single nucleotide polymorphisms in IL8 gene. Scientific Reports, 7(1), 6525. https://doi.org/10.1038/s41598-017-06575-4
De Castro, S. C. P., Leung, K.-Y., Savery, D., Burren, K., Rozen, R., Copp, A. J., & Greene, N. D. E. (2010). Neural tube defects induced by folate deficiency in mutant curly tail (Grhl3) embryos are associated with alteration in folate one-carbon metabolism but are unlikely to result from diminished methylation. Birth Defects Research. Part A, Clinical and Molecular Teratology, 88(8), 612-618. https://doi.org/10.1002/bdra.20690
Del Gobbo, G. F., Price, E. M., Hanna, C. W., & Robinson, W. P. (2018). No evidence for association of MTHFR 677C&T and 1298A&C variants with placental DNA methylation. Clinical Epigenetics, 10(1), 34. https://doi.org/10.1186/s13148-018-0468-1
Doudney, K., Grinham, J., Whittaker, J., Lynch, S. A., Thompson, D., Moore, G. E., Copp, A. J., Greene, N. D. E., & Stanier, P. (2009). Evaluation of folate metabolism gene polymorphisms as risk factors for open and closed neural tube defects. American Journal of Medical Genetics Part A, 149A(7), 1585-1589. https://doi.org/10.1002/ajmg.a.32937
Fang, Y., Zhang, R., Zhi, X., Zhao, L., Cao, L., Wang, Y., & Cai, C. (2018). Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of Northern China. Child’s Nervous System, 34(4), 725-729. https://doi.org/10.1007/s00381-018-3730-0
Greene, N. D.E., Stanier, P., & Copp, A. J. (2009). Genetics of human neural tube defects. Human Molecular Genetics, 18(R2), R113-R129. https://doi.org/10.1093/hmg/ddp347
Greene, Nicholas D E, & Copp, A. J. (2014). Neural Tube Defects NTDs: Neural tube defects. Annual Review of Neuroscience, 37, 221-242. https://doi.org/10.1146/annurev-neuro-062012-170354
Hayati, A. R., Zainal, A. I., Tan, G. C., Ong, L. C., & Khoo, T. B. (2008). MTHFR C677T Polymorphism as a Risk Factor of Neural Tube Defects in Malay: A Case Control Study. Medical Journal of Malaysia, 63(5), 379-383.
Hiraoka, M., & Kagawa, Y. (2017). Genetic polymorphisms and folate status. Congenital Anomalies, 57(5), 142-149. https://doi.org/10.1111/cga.12232
Kirke, P. N., Mills, J. L., Molloy, A. M., Brody, L. C., O’Leary, V. B., Daly, L., Murray, S., Conley, M., Mayne, P. D., Smith, O., & Scott, J. M. (2004). Impact of the MTHFR C677T polymorphism on risk of neural tube defects: case-control study. BMJ : British Medical Journal, 328(7455), 1535-1536. https://doi.org/10.1136/BMJ.38036.646030.EE
Kondo, A., Matsuo, T., Morota, N., Kondo, A. S., Okai, I., & Fukuda, H. (2017). Neural tube defects: Risk factors and preventive measures. Congenital Anomalies, 57(5), 150-156. https://doi.org/10.1111/cga.12227
Kryukov, G. V, Pennacchio, L. A., & Sunyaev, S. R. (2007). Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. American Journal of Human Genetics, 80(4), 727-739. https://doi.org/10.1086/513473
Leung, K.-Y., Pai, Y. J., Chen, Q., Santos, C., Calvani, E., Sudiwala, S., Savery, D., Ralser, M., Gross, S. S., Copp, A. J., & Greene, N. D. E. (2017). Partitioning of One-Carbon Units in Folate and Methionine Metabolism Is Essential for Neural Tube Closure. Cell Reports, 21(7), 1795-1808. https://doi.org/10.1016/j.celrep.2017.10.072
Li, K., Wahlqvist, M., & Li, D. (2016). Nutrition, One-Carbon Metabolism and Neural Tube Defects: A Review. Nutrients, 8(11), 741. https://doi.org/10.3390/nu8110741
Liu, J., Qi, J., Yu, X., Zhu, J., Zhang, L., Ning, Q., & Luo, X. (2014). Investigations of single nucleotide polymorphisms in folate pathway genes in Chinese families with neural tube defects. Journal of the Neurological Sciences, 337(1-2), 61-66. https://doi.org/10.1016/J.JNS.2013.11.017
Mohd-Zin, S. W., Marwan, A. I., Abou Chaar, M. K., Ahmad-Annuar, A., & Abdul-Aziz, N. M. (2017). Spina Bifida: Pathogenesis, Mechanisms, and Genes in Mice and Humans. Scientifica, 2017, 5364827. https://doi.org/10.1155/2017/5364827
O’Leary, V. B., Mills, J. L., Pangilinan, F., Kirke, P. N., Cox, C., Conley, M., Weiler, A., Peng, K., Shane, B., Scott, J. M., Parle-McDermott, A., Molloy, A. M., & Brody, L. C. (2005). Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association. Molecular Genetics and Metabolism, 85(3), 220-227. https://doi.org/10.1016/j.ymgme.2005.02.003
Olteanu, H., Munson, T., & Banerjee, R. (2002). Differences in the Efficiency of Reductive Activation of Methionine Synthase and Exogenous Electron Acceptors between the Common Polymorphic Variants of Human Methionine Synthase Reductase †. Biochemistry, 41(45), 13378-13385. https://doi.org/10.1021/bi020536s
Padmanabhan, N., Jia, D., Geary-Joo, C., Wu, X., Ferguson-Smith, A. C., Fung, E., Bieda, M. C., Snyder, F. F., Gravel, R. A., Cross, J. C., & Watson, E. D. (2013). Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell, 155(1), 81-93. https://doi.org/10.1016/j.cell.2013.09.002
Pietrzyk, J. J., Bik-Multanowski, M., Sanak, M., & Twardowska, M. (2003). Polymorphisms of the 5,10-methylenetetrahydrofolate and the methionine synthase reductase genes as independent risk factors for spina bifida. Journal of Applied Genetics, 44(1), 111-113. http://www.ncbi.nlm.nih.gov/pubmed/12590188
Raychaudhuri, S. (2011). Mapping rare and common causal alleles for complex human diseases. Cell, 147(1), 57-69. https://doi.org/10.1016/j.cell.2011.09.011
Relton, C., Wilding, C., Pearce, M., Laffling, A., Jonas, P., Lynch, S., Tawn, E., & Burn, J. (2004). Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population. Journal of Medical Genetics, 41(4), 256. https://doi.org/10.1136/JMG.2003.010694
Teo, Y.-Y., Sim, X., Ong, R. T. H., Tan, A. K. S., Chen, J., Tantoso, E., Small, K. S., Ku, C.-S., Lee, E. J. D., Seielstad, M., & Chia, K.-S. (2009). Singapore Genome Variation Project: a haplotype map of three Southeast Asian populations. Genome Research, 19(11), 2154-2162. https://doi.org/10.1101/gr.095000.109
van der Linden, I. J. M., den Heijer, M., Afman, L. A., Gellekink, H., Vermeulen, S. H. H. M., Kluijtmans, L. A. J., & Blom, H. J. (2006). The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida. Journal of Molecular Medicine, 84(12), 1047-1054. https://doi.org/10.1007/s00109-006-0093-x
van der Put, N., Eskes, T. K., & Blom, H. J. (1997). Is the common 677C-->T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? A meta-analysis. QJM, 90(2), 111-115. https://doi.org/10.1093/qjmed/90.2.111
Wang, Y., Liu, Y., Ji, W., Qin, H., Wu, H., Xu, D., Tukebai, T., & Wang, Z. (2015). Analysis of MTR and MTRR Polymorphisms for Neural Tube Defects Risk Association. Medicine, 94(35), e1367. https://doi.org/10.1097/MD.0000000000001367
Wilson, A., Platt, R., Wu, Q., Leclerc, D., Christensen, B., Yang, H., Gravel, R. A., & Rozen, R. (1999). A Common Variant in Methionine Synthase Reductase Combined with Low Cobalamin (Vitamin B12) Increases Risk for Spina Bifida. Molecular Genetics and Metabolism, 67(4), 317-323. https://doi.org/10.1006/mgme.1999.2879
Xu, J., & Sinclair, K. D. (2015). One-carbon metabolism and epigenetic regulation of embryo development. Reproduction, Fertility and Development, 27(4), 667. https://doi.org/10.1071/RD14377
Zhang, H., Guo, Y., Gu, H., Wei, X., Ma, W., Liu, D., Yu, K., Luo, W., Ma, L., Liu, Y., Xue, J., Huang, J., Wang, Y., Jia, S., Dong, N., Wang, H., & Yuan, Z. (2019). TRIM4 is associated with neural tube defects based on genome-wide DNA methylation analysis. Clinical Epigenetics, 11(1), 17. https://doi.org/10.1186/s13148-018-0603-z
Zhang, T., Lou, J., Zhong, R., Wu, J., Zou, L., Sun, Y., Lu, X., Liu, L., Miao, X., & Xiong, G. (2013). Genetic variants in the folate pathway and the risk of neural tube defects: a meta-analysis of the published literature. PloS One, 8(4), e59570. https://doi.org/10.1371/journal.pone.0059570
Zhu, H., Wicker, N. J., Shaw, G. M., Lammer, E. J., Hendricks, K., Suarez, L., Canfield, M., & Finnell, R. H. (2003). Homocysteine remethylation enzyme polymorphisms and increased risks for neural tube defects. Molecular Genetics and Metabolism, 78(3), 216-221. https://doi.org/10.1016/S1096-7192(03)00008-8
Published
How to Cite
Issue
Section
Categories
License
Copyright (c) 2020 Amelia Cheng Wei Tan, Siti Waheeda Mohd-Zin, Nur'Awatif Ishak, Meow-Keong Thong, Azlina Ahmad-Annuar, Abu Bakar Azizi, Noraishah Mydin Abdul-Aziz
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The observations and associated materials published or posted by NeurosciRN are licensed by the authors for use and distribution in accord with the Creative Commons Attribution license CC BY-NC 4.0 international, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
