A Germline Truncating VEGFB Mutation Causes Severe Familial Hyperlipidemia and Impairs Lipid Metabolism

BACKGROUND: Primary hyperlipidemia is a common metabolic disorder characterized by elevated plasma lipids, leading to fatty liver, acute pancreatitis, and increased cardiovascular risk. Although several causative genes have been identified, substantial genetic heterogeneity remains and the molecular etiology in many patients is unclear. Vascular endothelial growth factor B (VEGFB) regulates tissue fatty acid uptake and lipid metabolism, yet its mutations have not been reported in human hyperlipidemia. AIM: To identify the genetic cause of severe hyperlipidemia in a Chinese family and to functionally characterize the underlying variant. DESIGN: Family-based genetic and functional study. METHODS: We recruited a Chinese family with severe hyperlipidemia. The proband had an 11-year history of hyperlipidemia, complicated by fatty liver, latent glomerulonephritis, and recurrent acute pancreatitis. Whole exome sequencing (WES) was used to determine the genetic etiologies in this family. RESULTS: A novel heterozygous truncation mutation (NM_003377.5: c.361C>T; p.Q121*) of VEGFB gene was detected. Bioinformatics analysis predicted that this mutation leads to truncation of the VEGFB protein, impairing its dimerization and binding to the VEGFR1 receptor. Functional studies revealed reduced VEGFB protein abundance in mutation carriers, and knockdown of VEGFB in HepG2 cells disrupted the AMPK-mediated lipid oxidation pathway, resulting in triglyceride accumulation. CONCLUSIONS: WES was employed to investigate the genetic etiology of a family with hyperlipidemia, leading to the identification of a novel mutation in the VEGFB gene. Our findings established VEGFB as a candidate gene for primary hyperlipidemia, expanded its genetic landscape, and provided a new target for molecular diagnosis.