Genetic polymorphisms in the thioredoxin 2 (TXN2) gene and risk for spina bifida

Abstract

TXN2 encodes human thioredoxin 2, a small redox protein important in cellular antioxidant defenses, as well as in the regulation of apoptosis. Txn2 knockout mice fail to complete neural tube closure by E10.5 and die in utero. We hypothesized that genetic variation in human TXN2 gene may alter the function of the encoded protein in a manner associated with an increased risk for neural tube defects (NTDs). A DNA re-sequencing effort of the human TXN2 gene was taken. After a variation in the promoter was identified, the transcriptional activity of different alleles was investigated. The possible association between these variations and the risk of spina bifida was further evaluated in a subset of samples obtained from a large population-based case-control study in California in two different ethnicity groups, non-Hispanic white and Hispanic white. We identified a novel promoter insertion polymorphism located 9 base pairs upstream of the transcription start site of exon 1(−9 insertion). The GA, G and GGGA insertions were associated with a marked decrease of transcriptional activity when overexpressed in both U2-OS (an osteosarcoma cell line) and 293 cells (derived from human embryonic kidney). Further analysis revealed that the GA insertion was associated with increased spina bifida risk for Hispanic whites. Our study revealed a novel Ins/Del polymorphism in the human TXN2 gene proximal promoter region that altered the transcriptional activity and is associated with spina bifida risk. This polymorphism may be a genetic modifier of spina bifida risk in this California population.

Morphogenetic Variability as Potential Biomarker of Neurogenic Lesion Degree in Children with Spina Bifida

“…Neural tube closure is a process involving interactions between genes, where environmental factors play significant role, pointing out the multifactorial inheritance of the spina bifida entity [24]. Beside the environmental factors that were studied broadly in several studies [8,24], as well as some molecular genetic observations, including the correlation of certain mutations on X chromosome and its influence on the SB formation [3,10,[25][26][27][28], a population-genetic approach, as a new method, can give a new insight on etiology for individuals with spina bifida [4,29].…”

“…The etiology that governs formation of SB is still unknown, but there are studies implicating multifactorial origin [1,2]. Genetic components, both on populational and molecular levels, have been evaluated in the patients with SB [1,[3][4][5]. Additionally, the environmental and maternal factors, along with folate and homocisteine metabolism, are studied as potential factors in the etiopathogenesis of SB [1,[6][7][8].…”

Defectos del tubo neural y ácido fólico: patogenia, metabolismo y desarrollo embriológico. Revisión de la literatura

“…63 Los eventos comunes a los diversos factores de riesgo ambientales y genéticos, así como los polimorfismos genéticos asociados con la MTHFR, confluyen en los procesos de neurulación y en el metabolismo del folato/ homocisteína. Sin embargo, en los modelos animales de DTN no se han encontrado defectos en el metabolismo del AF, 64,65 indicando que aunque los defectos de la neurulación son los precursores de la manifestación clínica de los DTN y que la cinética enzimática disminuida de la MTHFR es un factor de riesgo genético-metabólico, la causa más temprana del disrafismo reside en eventos del desarrollo susceptibles a ser corregidos por la suplencia de AF tales como la supervivencia de las células neuroepiteliales por la reparación del ADN. Asimismo, el ácido fólico y la vitamina B12 (cobalamina) se relacionan con la síntesis y reparación de nucleótidos y son interme-diarios en la metilación de la homocisteína.…”

Inside the genome: understanding genetic influences on oxidative stress

“…Alleles A2 (GA insertion), A4 (G insertion), and A5 (GGGA insertion) display decreased transcriptional activity, attributed to additional SP1 binding sites. This suggests a potential association with heightened oxidative stress, indicating that individuals carrying these alleles may be predisposed to an imbalance in redox homeostasis ( Wen et al, 2009 ). Similarly, the rs4485648 polymorphism in intron one of the TXN2 gene is known to modulate oxidative stress-risk.…”