Spina Bifida - Genes and Signaling Pathways

Genes and Signaling Pathways

Introduction to Genetic Factors

Spina bifida does not follow a simple genetic pattern, but genetics are a significant piece of the puzzle. Researchers consider spina bifida a classic multifactorial disorder, involving the interaction of multiple genes with environmental factors (MedlinePlus Genetics, n.d.). Over the years, scientists have identified dozens of genes that might influence the risk of neural tube defects. These genes can be grouped into a few categories, such as those involved in folate metabolism, those involved in the developmental processes of neural tube closure, and others that maintain the structure of cells during embryo development. It’s important to note that no single gene mutation has been found to cause spina bifida in most cases (MedlinePlus Genetics, n.d.). Instead, common variations in many genes each might contribute a small increase in risk. If a baby inherits enough risk variants and is exposed to certain environmental factors (like low folate), the likelihood of spina bifida goes up.

MTHFR and Folate Metabolism

One of the most researched genes in spina bifida is MTHFR—methylenetetrahydrofolate reductase (MedlinePlus Genetics, n.d.). The MTHFR gene provides instructions for making an enzyme that plays a crucial role in processing folate (vitamin B₉) in the body (MedlinePlus Genetics, n.d.). Folate is needed to create DNA and other important molecules; it’s especially vital in rapidly dividing cells like those in a developing embryo. A well-known variant of MTHFR, often called C677T, results from a single-letter DNA change and leads to an enzyme that is somewhat less efficient. People who carry two copies of this variant (often noted as the “TT” genotype) have an enzyme that is less stable and works less well when folate levels are low (Shine Charity, n.d.). This can cause higher homocysteine levels and lower active folate in the blood, conditions which have been associated with a higher risk of neural tube defects. In fact, studies have shown that infants with the MTHFR 677 TT genotype are over-represented among spina bifida cases, suggesting it confers an increased risk (de Franchis et al., 2002). However, having the variant by itself is not destiny – folic acid supplementation can largely compensate for it (Shine Charity, n.d.). Research indicates that when mothers take adequate folic acid, the negative impact of the MTHFR variant is greatly reduced, and the risk of spina bifida drops significantly (Shine Charity, n.d.). In practical terms, this means even if someone has a “folate-processing gene issue” like the MTHFR variant, taking extra folic acid can help ensure the embryo still gets enough folate to properly close the neural tube. Thus, MTHFR illustrates how a gene and an environmental factor (folate nutrition) interact to influence spina bifida risk.

Planar Cell Polarity and VANGL2

Beyond folate-related genes, numerous genes directly involved in neural tube development have been studied. The closure of the neural tube is a complex process requiring cells to move, change shape, and adhere to each other in very precise ways. Several genes that guide these cellular behaviors have been linked to spina bifida when they malfunction. For example, genes in the planar cell polarity (PCP) pathway are crucial for neural tube closure. The PCP pathway helps cells orient themselves and coordinate their movement within the plane of a tissue. If this signaling is disrupted, the neural plate (the precursor to the neural tube) may not converge and zip up correctly. In mice, mutations in core PCP genes like VANGL2 cause a severe open neural tube defect (the “loop-tail” phenotype). In humans, rare mutations in VANGL1 or VANGL2 have been identified in some families affected by spina bifida (Galea et al., 2018). In one study, infants with spina bifida were found to have de novo (new) mutations in PCP pathway genes, and these mutations impaired how cells in the embryo connect and communicate (Shatto, 2025). The normal function of VANGL genes is to ensure cells at the neural plate borders can slide into place and allow the edges of the neural tube to meet and fuse. When VANGL or related PCP proteins are faulty, the closure process can stall, leading to an opening. These findings tie into a broader signaling context: the PCP pathway is a branch of the Wnt signaling family, a major cell communication system in development. Thus, spina bifida can result from disturbances in fundamental signaling cascades that govern embryonic morphology.

Image source: Galea et al. (2018, March 15). https://doi.org/10.1242/dmm.032219

Figure: Neural tube closure defects caused by Vangl2 mutation.

Compared to the control, embryos with disrupted VANGL2 function (Grhl3Cre;Vangl2^Fl/Fl^) show reduced neural fold elevation and altered cell morphology. This demonstrates how faulty planar cell polarity disrupts the biomechanics of neural tube closure (Galea et al., 2018).

Additional Developmental Genes

Another gene of interest is PAX3, a gene that helps regulate neural tube formation and is expressed in the early neural crest cells. In the Splotch mutant mouse (which has a Pax3 mutation), neural tube defects including spina bifida occur. While PAX3 mutations are not a common cause in humans, this illustrates the role of developmental genes – PAX3 normally turns on other genes needed for the neural folds to elevate and fuse. Mutations in human developmental genes like GLI3, CELSR1, FZD6, and others have also been implicated in certain cases of spina bifida or related defects, often in either animal models or rare human syndromes. Many of these genes integrate into networks like the Sonic hedgehog (SHH) signaling pathway (important for patterning the neural tube) or the Bone Morphogenetic Protein (BMP) pathway, etc. The patterning of the neural plate and its folding into the neural tube is heavily influenced by molecular signaling gradients. One key signal is BMP (Bone Morphogenetic Protein), which promotes epidermal (non-neural) fate in ectodermal cells. For the neural plate to form and bend, BMP signaling must be suppressed at the midline by antagonists like Noggin and Chordin, secreted by the notochord. This inhibition allows MHP cells to adopt a neural fate and undergo shape changes necessary for folding. So, while we often emphasize folate, there are multiple genetic pathways – from cell polarity, to cell cycle, to cell signaling – that must all function correctly to close the neural tube.

Highlighted Gene Functions

To highlight one gene's normal function and how its alteration leads to spina bifida, let's revisit MTHFR as an example in the metabolic category and VANGL2 as an example in the developmental signaling category:

MTHFR

This enzyme is part of the one-carbon metabolism cycle. Normally, MTHFR helps convert one form of folate into another (specifically 5,10methylenetetrahydrofolate to 5-methyltetrahydrofolate) (Shine Charity, n.d.). This reaction is necessary for producing methyl groups used in DNA synthesis and in regulating gene expression (via DNA methylation). MTHFR is expressed in many tissues, including the rapidly dividing cells of the embryo. If MTHFR activity is significantly reduced (due to genetic variants) and if folate supply is marginal, the embryo might not synthesize DNA fast enough in the neural tube cells or might misregulate gene expression needed for closure. This can lead to spina bifida. However, because folate is a vitamin we can supplement, the risk from MTHFR variants can be mitigated by ensuring high folate availability. In essence, MTHFR ties spina bifida risk to a biochemical pathway – it’s a gene-environment example where the gene’s effect (variant causing lower enzyme efficiency) leads to a problem (less folate in the right form) only if the environment (folate intake) is not optimal. When folate intake is high, even reduced-function MTHFR usually can keep up enough for normal development (Shine Charity, n.d.).

VANGL2

VANGL2 is a protein that resides in cell membranes and is a core component of the planar cell polarity pathway. Its normal function is to help cells communicate directional cues – essentially telling cells which way is “head to tail” in the plane of a tissue. In the context of the neural tube, VANGL2 is needed for the coordinated movement of cells that cause the neural groove to close. It is highly expressed in the neuroepithelial cells during the time of neural tube closure. If one copy of VANGL2 is mutated (as found in some human spina bifida cases) or both copies are knocked out (as in loop-tail mice), the result is failure of the caudal neural tube to close (Galea et al., 2018). On a cellular level, without proper VANGL2 function, cells don’t polarize correctly; the shaping and bending of the neural plate is abnormal, and the edges cannot fuse. This leads to an “open” neural tube – effectively spina bifida. VANGL2 interacts with other proteins (like Dishevelled, Prickle, Celsr) in the PCP pathway and connects to the wider Wnt signaling network which is fundamental in embryogenesis (Galea et al., 2018). The discovery of VANGL mutations in spina bifida patients demonstrates that even if folate is sufficient, disruptions in core developmental pathways can still cause NTDs. Interestingly, this knowledge opens up potential therapeutic questions – e.g., could drugs that modulate Wnt/PCP signaling reduce NTD risk in some genetic contexts? That remains to be seen.

Besides MTHFR and VANGL, researchers have looked at genes like SHH (sonic hedgehog) which patterns the ventral neural tube, TBX factors which are transcription factors needed for mesoderm development (spinal mesoderm issues could indirectly affect closure), and Collagen genes that affect connective tissue strength of the spinal canal, among many others. A theme emerging from genetic studies, especially with new high-throughput sequencing, is that a significant subset of spina bifida cases may be due to spontaneous (de novo) mutations in crucial developmental genes. In 2025, a groundbreaking study sequenced families with spina bifida and found that about 1/4 of patients had new mutations not present in their parents, which clustered in certain biological pathways (Shatto, 2025). These mutations often impacted how cells adhere and interact, reinforcing the idea that cell adhesion and communication are key to neural tube closure.

Environmental Factors

Environmental factors (teratogens) that cause spina bifida often do so by interfering with gene function or expression during development. For example, the drug valproic acid (an anti-seizure medication) is a known teratogen that can lead to spina bifida. Valproic acid is thought to inhibit enzymes called histone deacetylases (HDACs), which can alter the expression of genes during neural development. This may disrupt the expression of multiple genes needed for closing the neural tube. Additionally, valproate can affect folate metabolism. Thus, a single teratogen can have broad genetic and molecular effects – essentially “turning off” or misregulating the normal signaling pathways that orchestrate spinal development. Similarly, maternal diabetes creates a high-glucose environment that can cause oxidative stress in embryonic cells, which in turn can affect gene expression and cell survival in the neural tube. High temperature (fever) can lead to protein misfolding or cell stress responses that might impair the closure process. Each of these environmental factors interacts with the embryo’s genome, sometimes unmasking a vulnerability (for instance, an embryo with a mild PCP pathway mutation might normally still manage to close its neural tube, but if the mother has hyperthermia at a critical time, that added stress could tip the balance toward a defect).

In summary, spina bifida arises from a complex interplay of genes and molecular pathways. Key pathways implicated include those involved in folate metabolism (one-carbon cycle), planar cell polarity (Wnt/PCP signaling), and other developmental signaling routes (like SHH, BMP, etc.). Additionally, Sonic Hedgehog (SHH) plays a crucial role in reinforcing neural tube patterning. Secreted by the notochord and floor plate, Shh helps define the ventral neural tube, guiding the fate of motor neurons and interneurons. Disruptions to this signaling cascade—whether from gene mutations, environmental toxins, or nutritional deficiencies—can interfere with closure or lead to abnormal cell differentiation, contributing to spina bifida phenotypes. At least one gene, MTHFR, shows how metabolic genetics ties into a nutritional preventive measure (folate), whereas genes like VANGL2 highlight core developmental biology mechanisms. The broad goal of research in this area is to map out the “circuit diagram” of neural tube closure: identifying every important gene and pathway, and understanding how external factors influence them. This knowledge not only helps explain why spina bifida happens but also suggests where we might intervene – for instance, by recommending vitamins (to bypass metabolic bottlenecks) or by developing new therapies that could modulate pathways during that critical window of embryo development.

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