Abstract : The classic model of tumor suppression implies that malignant transformation requires full "two-hit"
inactivation of a tumor-suppressor gene. However, more recent work in mice has led to the proposal of a
"continuum" model that involves more fluid concepts such as gene dosage-sensitivity and tissue specificity.
Mutations in the tumor-suppressor gene von Hippel-Lindau (VHL) are associated with a complex spectrum of
conditions. Homozygotes or compound heterozygotes for the R200W germline mutation in VHL have Chuvash
polycythemia, whereas heterozygous carriers are free of disease. Individuals with classic, heterozygous VHL
mutations have VHL disease and are at high risk of multiple tumors (e.g., CNS hemangioblastomas, pheochromocytoma,
and renal cell carcinoma). We report here an atypical family bearing two VHL gene mutations in cis
(R200W and R161Q), together with phenotypic analysis, structural modeling, functional, and transcriptomic
studies of these mutants in comparison with classical mutants involved in the different VHL phenotypes. We
demonstrate that the complex pattern of disease manifestations observed in VHL syndrome is perfectly
correlated with a gradient of VHL protein (pVHL) dysfunction in hypoxia signaling pathways. Thus, by studying
naturally occurring familial mutations, our work validates in humans the "continuum" model of tumor
suppression.
