46. Tumour suppressor genes II. NF1, NF2, VHL, WT-1 and WT-2. Related syndromes

Last updated on December 13, 2018 at 14:48


NF1 is a gene that codes for a protein called neurofibromin. The physiological function of this protein is to stimulate the GTPase activity of Ras, inhibiting it. Mutations in the gene are associated with neurofibromatosis type 1, a disease with many symptoms. The mutation causes tumors to form along the nervous system that can form anywhere in the body. Diagnosis of the disease requires two or more of the following criteria:

  • Brownish spots on the body, called café au lait spots
  • Presence of neurofibromas
  • Presence of a plexiform neurofibromas
  • Axillary or inguinal pigmentation
  • Optic glioma
  • Lisch nodules on the iris
  • Bone lesions
  • Neurofibromatosis type 1 in close relatives

NF2 is a gene that codes for a protein called merlin. Mutations in this gene causes neurofibromatosis type 2, which is characterized by bilateral benign tumors of the nerve sheathe of the vestibulocochlear nerve, so-called Schwannomas. Some meningiomas and ependymomas have also shown mutations in NF2.


VHL, or von Hippel-Lindau is a gene that codes for a transcription factor with the same name. The protein should be familiar from biochemistry, where it’s involved in the cell’s response to hypoxia together with HIF-1α. When the cell is normoxic (no hypoxia) is VHL degraded before it can do anything. If there’s hypoxia will VHL not be degraded but instead travel into the nucleus and activate genes responsible for cell growth and angiogenesis.

Germ-line mutations of the VHL gene causes von Hippel-Lindau syndrome, which is characterized by:

  • Hereditary renal cell carcinoma
  • Pheochromocytoma
  • Hemangioblastomas in the CNS
    • Especially in the cerebellum and spinal cord
  • Retinal angiomas
  • Renal cysts

WT1 is a tumor suppressor gene that codes for a protein with the same name. The WT1 protein is essential for renal and gonadal development. Problems with this gene is associated with two syndromes, WAGR syndrome and Denys-Drash syndrome.

WAGR syndrome (Wilms tumor, Aniridia, Genital abnormalities and mental Retardation) is a syndrome people with a germline deletion of one of the WT1 alleles have. 1/3 of patients with WAGR will acquire the “second hit” mutation where the other WT1 allele is mutated as well, causing them to develop Wilms tumor. Wilms tumor, or nephroblastoma, is a primary kidney tumor that is much more common in children than in adults.

Danys-Drash syndrome is a syndrome where there is a germline mutation (not a deletion) in one of the WT1 alleles. Patients with D-D syndrome have 90% chance of developing Wilms tumor. People with this syndrome also have:

  • Gonadal dysgenesis
  • Early nephropathy
  • Increased risk of gonadoblastoma

Only 15% of patients with Wilms tumor that don’t have any of the above syndromes have a WT1 mutation.


WT2 is another tumor suppressor gene that is also involved in Wilms tumor. It’s associated with Beckwith-Weidemann syndrome, which is characterized by:

  • Hemihypertrophy (one side of the body is larger than the other)
  • Macroglossia
  • Organomegaly
  • Omphalocele
  • Adrenal cytomegaly
  • Wilms tumor

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2 thoughts on “46. Tumour suppressor genes II. NF1, NF2, VHL, WT-1 and WT-2. Related syndromes”

  1. Hey,
    For VHL the lecture say:
    In the presence of oxygen, HIF1α binds to VHL protein leading to proteosomal degradation
    – In hypoxia HIF1α does not bind to VHL, travels to the nucleus, turns on many genes responsible for
    cellular growth and angiogenesis, like VEGF and PDGF → vascular proliferation

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