FERNANDEZ Maria Celia
VHL-P138R and VHL-L163R novel variants: mechanisms of VHL pathogenicity involving HIF-dependent and HIF-independent actions
CECILIA MATHÓ; MARIA CELIA FERNÁNDEZ; JENNER BONANATA; XIAN-DE LIU; AYELÉN MARTIN; ANA VIEITES; GABRIELA SANSÓ; MARTA BARONTINI; ERIC JONASCH; ELENA LAURA COITIÑO; PATRICIA ALEJANDRA PENNISI
Frontiers in Endocrinology
The von Hippel?Lindau (VHL) disease is an autosomal dominant cancer syndrome caused Q48by 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 beendiscovered, the most described function of pVHL is to recognize and target hypoxiainducible factor (HIF) for degradation. This work comprises the functional characterizationof two novel variants of the VHL gene (P138R and L163R) that have been described in our Q14center in patients with VHL disease by in vitro, in vivo, and in silico approaches. In vitro, wefound that these variants have a significantly shorter half-life compared to wild-type VHLbut still form a functional VBC complex. Altered fibronectin deposition was evidenced forboth variants using immunofluorescence. In vivo studies revealed that both variants failedto suppress tumor growth. By means of molecular dynamics simulations, we inspected insilico the nature of the changes introduced by each variant in the VBC complex. We havedemonstrated the pathogenicity of P138R and L163R novel variants, involving HIFdependent and HIF-independent mechanisms. These results provide the basis forfuture studies regarding the impact of structural alterations on posttranslationalmodifications that drive pVHL?s fate and functions.