Project title

Impact of genetic defects in folate metabolism on embryonic development and congenital anomalies 

Supervisors


Background

Approximately 1 in every 20 babies is affected by a serious structural abnormality. These congenital anomalies (birth defects) include neural tube defects, cleft palate, and heart defects. They are the most common cause of death in infants and children and can have a severe long-term impact on surviving individuals [1]. Understanding the causes and mechanisms underlying congenital anomalies offers potential for improved genetic diagnosis, treatment, and prevention. Causes of birth defects include genetic mutations, including single and multigenic conditions, and environmental factors, such as drug exposure or nutrition[2].

Several birth defects are associated with impaired folate metabolism, a network of reactions that is influenced both by genetic mutations and maternal nutrition. For example, inadequate intake of folate or vitamin B12 increases the risk of neural tube defects [3], while mutation of genes such as GLDC or AMT can cause neural tube defects or hydrocephalus [4, 5]. We have developed novel mouse models that also implicate folate metabolism genes in cleft palate, limb anomalies, and congenital heart defects.

Aims and objectives

The overall objective of this project is to understand how impaired function of key steps of folate metabolism can cause specific structural malformations in the developing embryo. This project will make use of recently developed mouse models to determine whether defects that arise in different tissues and at different stages involve shared and/or distinct molecular and cellular mechanisms. 

Aims will be to:

  1. Determine whether impaired folate metabolism causes abnormal specification, migration, or differentiation of neural crest cells.
  2. Test whether specific transcriptional signature(s) are associated with distinct tissue abnormalities and/or specific genetic defect in folate metabolism.
  3. Investigate whether folate-related mutations lead to tissue-specific alterations in cell proliferation and/or oxidative stress
  4. Test whether anomalies are preventable by nutrient supplementation.


Methods

This project will use mouse and cellular models with genetic alterations in key folate-metabolising enzymes (established in our laboratory). These include novel models carrying human disease-causing mutations, conditional models (where genetic loss-of-function is inducible in selected tissues/stages) and reporter lines which allow tracing of knockout cells. The project will be based in a multi-disciplinary group with opportunity to apply mouse embryology, cell-based assays, advanced fluororescence microscopy, transcriptomics, bioinformatics and biochemical assays, depending on student areas of interest.

Timeline

  • Year 1: NCC analysis; Sample collection for RNA-sequencing.
  • Year 2: Transcriptome analysis/validation.
  • Year 3: Preventive strategies; Prepare thesis and manuscript(s).

 

References

  1. Twigg, SRF, et al., The power of mouse models in the diagnostic odyssey of patients with rare congenital anomalies. Mamm Genome, 2025. 36: 354-362.  
  2. Nikolopoulou, E, et al., Neural tube closure: cellular, molecular and biomechanical mechanisms. Development, 2017. 144: 552-566.
  3. Sudiwala, S, et al., Cellular mechanisms underlying Pax3-related neural tube defects and their prevention by folic acid. Dis Model Mech, 2019. 12:dmm042234.
  4. Pai, YJ, et al., Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice. Nat. Commun, 2015. 6: 6388.
  5. Santos, C, et al., Impaired folate 1-carbon metabolism causes formate-preventable hydrocephalus in glycine decarboxylase-deficient mice. J Clin Invest, 2020. 130: 1446-1452.


Who should students contact?

Nick Greene (n.greene@ucl.ac.uk)

Research topic

Developmental Biology, Genetics