Unraveling the impact of VHL Exon 2 mutations identified in Erythrocytosis or von Hippel-Lindau disease, identified hnRNP F and hnRNP AB as new RNA-Binding Proteins involved in VHL splicing.

ABSTRACT: This study explores the impact of mutations in the exon 2 of the von Hippel-Lindau (VHL) gene, associated with erythrocytosis or von Hippel-Lindau disease. We analyzed 15 genetic variants, including missense and synonymous mutations, to assess their effects on VHL protein stability and splicing. Using in silico predictions and functional assays, we found that specific mutations reduce protein stability, induce exon skipping and can cause a shift in the splice donor site. This study highlighted new exonic splicing regulatory regions. Notably, by performing RNA-protein pull down we identified two novel RNA-binding proteins, hnRNP F and hnRNP AB, as key regulators of VHL splicing. Our findings reveal the limitations of current splicing prediction tools in recognizing exonic splicing enhancer (ESE) or silencer (ESS) sequences and suggest that mutations can differentially affect disease phenotypes by influencing both protein stability and splicing. These insights enhance our understanding of the molecular mechanisms underlying VHL-associated disorders, delimitate new regulatory regions and demonstrates the role of new RNA-binding proteins in VHL splicing regulation.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hela Cell

SUBMITTER: Marjorie Leduc  

LAB HEAD: Betty Gardie

PROVIDER: PXD056515 | Pride | 2025-09-25

REPOSITORIES: Pride