Abstract
Maternal genetic variants of enzymes in folate–homocysteine metabolic network are significantly correlative with the risk of spina bifida. To survey the genetic causality, the genotypes of three women having spina bifida fetuses from two unrelated Chinese families were screened in candidate alleles. Polymerase chain reaction, capillary electrophoresis and Sanger sequencing were employed to recognize the allelic variation. A trinucleotide deletion (c.4_6delAGG) was identified in the first exon of MTRR. All the three women showed the novel clinical variation including one heterozygous and two homozygous. The siblings who had healthy babies from the same families did not harbor the variation. In the unaffected control individuals, the variant was also not observed. Eukaryotic expression and bioinformatics techniques were utilized to explore the molecular pathogenesis of the potential genetic risk of developing spina bifida. Exceptionally, the functional examination revealed that the Arg2del variant kept subcellular localization unaltered with catalytic activity intact, but failed to efficiently activate MTR compared with the wild type. Genetic disorder of folate and homocysteine metabolism during pregnancy is believed to be associated with folate-sensitive neural tube defects. The report highlights that the inframe deletion in MTRR exon 1 could be a high risk factor susceptibility to spina bifida.
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Acknowledgements
We gratefully acknowledged all the patients, family members and control participants in providing specimens and clinical data for this study. The work was funded by the grants from Chongqing Municipal Education Commission (KJ080301), Chongqing Science & Technology Commission (CSTC, 2010BB5366) and National Natural Science Foundation of China (NO. 20803098).
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Xiao-lu Dai and Gui-cen Liu are co-first authors.
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Fig. s1
Pedigrees of the two families. In the family trees, the black circles represent the females who experienced spina bifida-affected pregnancy. The white circles signify the unaffected ones. Lack of allele information, the male or female mutation carrier could not be distinguished in the both families. The pedigree of family 1 is displayed on the left, family 2 on the right. The black arrows refer to the probands in the pedigrees. (TIFF 17592 kb)
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Zhang, J., Dai, Xl., Liu, Gc. et al. An Inframe Trinucleotide Deletion in MTRR Exon 1 is Associated with the Risk of Spina Bifida. Neuromol Med 19, 387–394 (2017). https://doi.org/10.1007/s12017-017-8452-z
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DOI: https://doi.org/10.1007/s12017-017-8452-z