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

NF1

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

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

VHL, or von Hippel-Lindau is a gene that codes for a protein with the same name. Its function is to break down the transcription factor HIF-1α if the cell is not hypoxic. The protein should be familiar from biochemistry. When the cell is normoxic (no hypoxia) will VHL degrade HIF-1α before it can do anything. If there’s hypoxia will VHL not degrade HIF-1α, which allows HIF-1α to travel into the nucleus, where it functions as a transcription factor 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

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

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