The EFTUD2 gene encodes the EFTUD2 protein, a core component of the pre-messenger RNA splicing machinery. Mutations in EFTUD2 causing haploinsufficiency lead to aberrant mRNA splicing which manifest in a craniofacial malformation, the Mandibulofacial Dysostosis Guion-Almeida type (MFDGA). EFTUD2 mutation was shown to result in downregulation of glycolytic genes in a mouse cell line, hinting at a role of metabolic processes in craniofacial malformations. The role of EFTUD2 in regulating splicing events required for the innate immune response during hepatitis B virus (HBV) infection and liver cancer has also been documented.
Research questions:
1. How do variants in the EFTUD2 gene affect metabolic process and result in a craniofacial malformation?
2. How do variants in the EFTUD2 gene modulate hepatitis B virus infection resulting in liver cancer?
Objectives:
1. We will extract variants present in the EFTUD2 gene from whole genome sequencing data. We will perform gene- and variant-based association analysis for congenital abnormalities, especially craniofacial malformation. Analysis will also be conducted for metabolic biomarkers in blood and urine data. Variants found will be compared with public datasets. Novel variants will be analysed computationally for their probability to cause haploinsufficiency. Variants predicted to cause haploinsufficiency by splicing defects will be confirmed using cell culture models of splicing. To support findings of EFTUD2 variant’s effect on metabolic perturbation, a metabolomic analysis of a cell line model of EFTUD2 mutation will be performed.
2. We will identify variants present in the EFTUD2 gene and analyse their correlations with HBV infection and liver cancer. We will utilise Hepatitis B virus antigens, blood biochemistry, and liver MRI data to establish hepatitis B and liver cancer status. We will then analyse the correlation between EFTUD2 gene variants and hepatitis B & liver cancer status.