Von Hippel-Lindau Syndrome (VHL) Presented by Kelley Montoya March 20, 2003

Objectives VHL—Description of the disease Biochemistry VHL Conditions of normal VHL Mutations and Effects of VHL

What is VHL ? Dominantly inherited cancer syndrome Predisposition to tumors of the: Eyes Central Nervous System (CNS) Kidneys Adrenal Chromaffin cells

What is VHL? Tumor suppressor gene On cellular level it works as a simple recessive Inherited as an autosomal dominant Affects an estimated 1 in 36,000 people Mean onset age is 26.3 with a penetrance o 97% by age 60

What is VHL?

Clear Cell Carcinoma Normal cellsCancer cells

Biochemistry of VHL Mapped to Chromosome 3 in the region 3p25-p26 Encodes a protein called pVHL consisting of 213 amino acids Is a component of an protein complex known as an E3 ubiquitin ligase What do action do ubiquitin ligases perform?

Biochemistry of VHL This complex ubiquitinates HIF-1α (Hypoxia Inducible Factor), and leads to is subsequent proteosomal degradation HIF-1α is a transcription factor that promotes other transcription factors (esp VEGF) Loss of Function of pVHL leads to stabilization of HIF-1α (transcription factor) even under normoxic conditions (normal oxygen presence) What is hypoxia?

Biochemistry of VHL Conditions of Under Normal VHL Production

Biochemistry of VHL Under normoxic conditions HIF-1α is constantly being degraded Under anoxic conditions (low oxygen) HIF-1α is not destroyed leading to activation of transcription factors such as GLUT-1, PDGF-B and VEGF (vascular endothelial growth factor)

Mutations in pVHL Mutations usually occur in the two protein binding domains of VHL, either α and β Mutations include Missense, frameshift nonsense and splice junction mutations

Effects of VHL Over production of HIF-1α induces transcription factors involved in angiogenesis (growth of blood vessels) Thus sufferers of VHL develop highly vascularized tumors