Resumen:
Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the VHL
gene. This gene, located in the 3p25-26 chromosome, is a tumor suppressor gene associated with the inhibition
of angiogenesis and apoptosis, cell cycle exit, fibronectin matrix assembly, and proteolysis. To define the
molecular basis of VHL in a Spanish population, we studied 33 patients suspected of suffering familial or de
novo VHL disease and two familial pheochromocytoma cases. Sequence analysis of the coding regions of the
VHL gene revealed germline sequence variants in 68.7% (24 out of 35) of the patients, and four of them
presented with undescribed germline alterations: g.5429_5430insG, p.Leu128Arg, p.Tyr175Cys, and
p.Tyr175Asn. For the remaining 11 patients who showed negative for point mutations, we performed Southern
blot analysis and detected gross rearrangements in eight cases (22.8% of the index cases). Our results support
the relevance of VHL gene analysis in familial pheochromocytoma cases and also in those with no familial
history. In order to investigate the relevance of different amino acid changes in the VHL phenotype, we also
analyzed the genotype¿phenotype correlations using structural analysis to assess protein stability and complexes.
The association of clear cell renal carcinoma (CCRC) development with a relatively high loss of structural
stability in pVHL missense-mutants was consistent. Structural stability data in the genotype¿phenotype
correlations therefore provides us with a better understanding of VHL clinical implications.
