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ORIGINAL ARTICLE
Year : 2019  |  Volume : 14  |  Issue : 1  |  Page : 16-19
 

Molecular basis of spina bifida: Recent advances and future prospectives


1 Department of Paediatrics, All India Institute of Medical Sciences (AIIMS), New Delhi, India
2 Department of Radiology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
3 Department of Physical Medicine and Rehabilitation, All India Institute of Medical Sciences (AIIMS), New Delhi, India
4 Department of Paediatric Surgery, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Date of Web Publication18-Jun-2019

Correspondence Address:
Dr. Mayadhar Barik
Department of Paediatric Surgery, Sir APJ Abdul Kalam and Tejaswini Awardee, Senior Scientific Advisor and Editor-in-Chief, All India Institute of Medical Sciences (AIIMS), New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JPN.JPN_20_19

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   Abstract 

Background: Spina bifida (SB) (spinal neural tube [NT] defects) is basically caused by an abnormality at the closure of the NT. Materials and Methods: Molecular researchers have now got new etiopathogenesis of the defective neural tube closure. Although molecular mechanisms in the SB is really important taxation for further work. We understand through the unique novel mutant responsible genes and modifying genes and included the different molecular aspects of SB from the available tools and databases and excluded the case reports. Statistical Analysis: We use here simple statistics (percentage, mean, median, and average) through the Statistical Package for the Social Sciences (SPSS), version 14, and found P > 0.0001 to be significant. Results: We have reported that the majority of 90% genes are responsible in SB and their associated diseases. These innovative unique patterns of responsible genes attached with the result abnormalities at the neuronal and non neuronal tissues are equally important for the SB and NTC. Conclusion: Our present ideology is aiming to understand the inductive and direct interactions of the downstream target sites among responsible regulating genes (RRGs). It is an unique pattern of genetic roadmap to control and guides the neurulation and may provide further insights into the causes of SB and may help to develop new molecular-targeted therapy (MTT).


Keywords: New tools, genes, genome-wide association study, neural tube closure, molecular-targeted therapy, spina bifida


How to cite this article:
Panda PK, Mallik KC, Patel R, Barik M. Molecular basis of spina bifida: Recent advances and future prospectives. J Pediatr Neurosci 2019;14:16-9

How to cite this URL:
Panda PK, Mallik KC, Patel R, Barik M. Molecular basis of spina bifida: Recent advances and future prospectives. J Pediatr Neurosci [serial online] 2019 [cited 2019 Sep 22];14:16-9. Available from: http://www.pediatricneurosciences.com/text.asp?2019/14/1/16/260615





   Introduction Top


Spina bifida (SB) is a birth abnormality, including failure of closure at the spinal level (SL), craniorachischisis, failure of neural tube closure (NTC), body axis, exencephaly, and failure of the cranial neural folds, and represents a great challenge in the regulation of cell and tissue behaviors.[1] The maternal genetic variants of enzymes in folate–homocysteine metabolic network are associated with the risk of SB already documented.[2] Bioinformatics techniques are now used to explore the molecular etiopathogenesis of the potential genetic risk pattern of developing SB; genomic test revealed that Arg2del variant kept subcellular localization unaltered within the catalytic activity intact and failed to efficiently activate 5-Methyltetrahydrofolate-Homocysteine Methyltransferase (MTR) compared with the wild type.[3] SB is the genetic disorder of folate and homocysteine metabolism (FHM) during pregnancy and is associated with folate-sensitive neural tube defects (FSNTDs) located in-frame deletion in methionine synthase reductase (MTRR) exon 1 as higher risk factor susceptibility to SB.[4] SB frequency is approximately 1–3 in 1000 live births in US.[5] In India, it is approximately 3.9–8.8 per 1000 live births.[6] Neural tube (NT) malformations involving the spinal cord and the vertebral arches are referred to as SB.[7]

SB involved within the protrusion of the spinal cord and/or meninges through a defect in the vertebral arch at the level of the lesion, interruption of the spinal cord at the site of the spina bifida defect (SBD) causes paralysis of the legs, incontinence of urine and feces, anesthesia of the skin, and abnormalities of the hips, knees, and feet. Abnormalities seen in children with SB include hydrocephalus and the Arnold–Chiari type II malformation.[8] Molecular basis of SB is a complex and heterogeneous condition. Grainyhead-like genes represent candidates for the SB and exencephaly; carrying loss-of-function alleles of Grhl2 or Grhl3 expression in bacterial artificial chromosome–mediated transgenesis prevents SB but Grhl3 overexpression at the Vangl2Lp allele causes SB.[9]

Folic acid supplements (FASs) helps to prevent the SB, NTDs, by stimulating the methylation reactions, methylome analysis for patients with myelomeningocele (MMC) by candidate CpG analysis for HOX genes associations at HOXB7 hypomethylation in MMC was found.[10] Leukocyte methylome data CpG-specific methylation replicated candidate genes are ABAT, CNTNAP1, SLC1A6, SNED1, SOX18, TEPP within the MMC patients respectfully.[11] Genome-wide methylation study observed that leukocytes in patients with NTDs and SB had SOX18 gene sequence that resulted in hypomethylation, which interplayed with environmental and epigenetic factors to cause NTDs and SB.[12]

The tumor suppressor protein Scribble (SCRIB) plays conserved role in cell polarity. The mutations pattern at SCRIB SADH domains is associated with SB and cancer.[10] The water-insoluble proteins are located on the surface of rubber particles in Hevea brasiliensis latex. One particle, 14.6 kd protein (Hev b 1), seen on large rubber particles (>350mm in diameter) and second particle, 24 kd protein (Hev b 3), found mainly on small rubber particles (average diameter, 70nm) are recognized by the immunoglobulin E in the patients with SB and latex allergy.[11]


   Materials and Methods Top


SB (spinal neural tube defects [NTDs]) basically is caused by an abnormality at the closure of the NT.

Molecular researchers were trying to know the new etiopathogenesis of the SB (spinal NTDs) and defective NTC.

Inclusion criteria: We included different molecular aspects of SB from available tools and databases.

Exclusion criteria: We excluded case reports and irrelevant studies.

Statistical analysis: We used simple statistics (percentage, mean, median, and average) through the Statistical Package for the Social Sciences (SPSS) software, version 15, SPSS Inc. 2006, Illinois, Chicago, and found P >0.0001 to be significant.


   Results Top


Genetic disorder of FHM during pregnancy is believed to be associated with the FSNTDs and SB. The report highlighted that the in-frame deletion in MTRR exon 1, a high-risk factor susceptible to the SB, is more than 90% of the original contributions.[12]


   Discussion Top


Exogenous retinoic acid induces the anterior (anencephaly and exencephaly) and posterior (SB) NTDs depending on the developmental stage of treatment.[13] Informative bio markers retinoic acid-treated wild-type and RARgamma-/- embryos indicated that treatment of wild-type embryos led to decrease the caudal expression, mesodermal biomarkers examined for brachyury, wnt-3a, cdx-4 somite, neuroepithelial, notochord, floorplate, and hindgut markers were unaffected.[14] Transcripts encoding mP450RAI, a cytochrome P450, catabolize retinoic acid, abundant in the retinoid-poor region caudal embryo, and generate posterior mesoderm derivatives in part by affecting brachyury expression.[15]

GRHL3 in the whole gene and the transactivation region in the data of the patients with SB provide a strong role as a predisposing factor to SB and help to dissect the complex etiology and pathogenic mechanisms of these malformations.[16] DVL1/2 mRNA levels are correlated with the levels of serine/threonine protein kinase, MARK2, and cases with human lumbosacral and SB.[17]FZD3 gene and planar cell polarity signaling pathway in convergent extension are involved with genetic and epigenetic mechanisms associated with human NTDs, but DNA methylation had important role in FZD3 gene, that is, to express and regulate SB.[18]

The transcription regulatory regions of TRIM26 and GNAS were at the hypomethylation status located in SB placenta but protein levels of TRIM26 and GNAS were elevated only in the SB placenta but not in the SB-affected fetuses. In CHO cells are deficienting in dihydrofolate reductase and treated with 5-aza-2’-deoxycytidine, the findings regarding the protein levels of GNAS and TRIM26 suggested that epigenetic status of genes in placenta helps in the development of NTDs.[19]

The small molecules, microRNA-7 (miR-7), microRNA-375 (miR-375), and microRNA-451 (miR-451), downregulate 14-3-3ζ. p53 expression is downstream of 14-3-3ζ and downregulates the reduction of 14-3-3ζ expression, the expression of miR-451, miR-375, and p53 is increased in SB in rat fetuses. Expression of 14-3-3ζ in the excessive apoptosis has major role in the SB due to over-expression of miR-451 and miR-375, consequent upregulation of p53 might further promote apoptosis in SB.[20] Novel missense mutation (p.A1257T) was detected in control samples, and it was predicted to be benign rare deleterious mutation of SCRIB, which contribute to the multifactorial risk for human SB [Table 1].[17],[21] In both animals and humans, PAX3 and T (brachyury) are the candidate genes for SB.[22]
Table 1: Majority of responsible genes involved with SB, NTDs, NTC

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   Recent Advances and Future Prospective Top


Dorsal spinous process schisis is a rare vertebral abnormality recognized by X-rays in the imaging study of the lung parenchyma anatomical variation; T1 SB occulta is also seen few times.[23] SB as the second most common group of congenital anomalies may be diagnosed by prenatal ultrasonography and may be associated with chromosomal abnormalities, including full and partial aneuploidies with syndromic SB associated with partial 3q duplication and partial 5p deletion, and emphasizes the consistency in the prenatal sonographic feature of SB in consecutive pregnancies with fetuses associated with the partial trisomy 3q (3q26.1-qter) and partial monosomy 5p (5p13.33-pter). The use of molecular cytogenetic technologies, such as array comparative genomic hybridization and fluorescence in situ hybridization, is important for clarifying any type of unbalanced chromosome rearrangement, which is one of the positive sides of investigation of SB and NTC.[24] PDGFRα downstream effectors, PI3K, are essential for cell migration of a somite-derived dorsal mesenchyme, and disruption of receptor signaling in these cells leads to SB[25] Maternal use of antiepileptic drugs (AEDs) during pregnancy is associated with major congenital malformations in children, certain AEDs are associated with increased rates of congenital malformations (SB, cardiac anomalies).[26]

Limitations: More studies will be required to determine whether these variants are influencing the risk of SB in Indian prospective.


   Conclusion Top


We concluded that direct interactions of the downstream target sites among few responsible regulating genes’ unique pattern of biology and their genetic road map control guide the neurulation and provide further insights for the causes of SB and help to develop new molecular-targeted therapy. The spectrum of mutant combined evidence in mutant models supports the congenital anomalies that may originate from perturbations of mesoderm specification, epithelial-mesenchymal transition, and mesodermal cell migration, which are responsible in molecular pathways needed to improve strategies for the prevention of major structural birth defects. Original studies will be required to determine whether these variants are influencing the risk of SB in Indian patient or not and this is stillan interesting research area that need to be improved through next-generation sequencing or genome wide association study or recent new innovative tools and techniques.

Acknowledgement

We would like to thank our teachers who guided and promoted us for innovation and research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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[PUBMED]  [Full text]  
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