VHL-P138R and VHL-L163R novel variants: mechanisms of VHL pathogenicity involving HIF-dependent and HIF-independent actions


** FIGURE 5. Front. Endocrinol. 13:854365. https://doi.org/10.3389/fendo.2022.854365


Von Hippel-Lindau disease is an autosomal dominant cancer syndrome caused by mutations in the VHL tumor suppressor gene. VHL protein (pVHL) forms a complex (VBC) with Elongins B-C, Cullin2 and Rbx1. Although other functions have been discovered, the most described function of pVHL is to recognize and target hypoxia inducible factor (HIF) for degradation.
This work comprises the functional characterization of two novel variants of the VHL gene (P138R and L163R) that have been described in our center in patients with VHL disease by in vitro, in vivo and in silico approaches.
In vitro, we found that these variants have a significantly shorter half-life compared to wild type VHL, but still form a functional VBC complex. Altered fibronectin deposition was evidenced for both variants using immunofluorescence. In vivo studies revealed that both variants failed to suppress tumor growth. By means of molecular dynamics simulations, we inspected in silico the nature of the changes introduced by each variant in the VBC complex.
We have demonstrated the pathogenicity of P138R and L163R novel variants, involving HIF dependent and HIF independent mechanisms. These results provide the basis for future studies regarding the impact of structural alterations on post translational modifications that drive pVHL’s fate and functions.


Authors: Cecilia Mathó, Celia Fernández, Jenner Bonanata, Xian-De Liu, Ayelén Martin, Ana Vieites, Gabriela Sansó, Marta Barontini, Eric Jonasch, Elena Laura Coitiño and Patricia A. Pennisi.

Cite: VHL-P138R and VHL-L163R novel variants: mechanisms of VHL  pathogenicity involving HIF-dependent and HIF-independent actions. Front. Endocrinol. 13:854365.
⇒ https://doi.org/10.3389/fendo.2022.854365


** FIGURE 5 | 3D representative structures from MD simulations. (A) VBC complex with pVHL : HIF-1a and pVHL : EloC interfaces where variants are located circled and evidencing relevant residues. (B, C) Overlapped representative structures for the most populated clusters from 400-ns MD simulation under normoxia. Circled residues correspond to pVHL variants amino acids P138R and L163R in (B, C), respectively. Color code: green, wild type pVHL; yellow, P138R pVHL variant; red, L163R pVHL variant.