Von Hippel-Lindau Disease
by Jeff Allred
Von Hippel-Lindau Disease (VHL), although once thought to be rare, is one
of the most common familial cancers. VHL disease is caused by a mutation
in a gene located on the short arm of chromosome 3 responsible for tumor
suppression. The genetic mutation causes capillary growth to go uncontrolled
in parts of the body that are particularly rich in blood vessels. The uncontrolled
growth of this vascular tissue causes the capillaries to form knots. These
small knots are called angiomas, or hemangioblastomas. Cysts may also grow
Dr. Eugene Von Hippel described angiomas in the eye in 1904. Many years
later in 1926, Dr. Arvid Lindau described hemangioblastomas of the cerebellum
and spine. Their names are usually associated with their respective areas
In June 1993 the VHL gene was identified (Science May 28, 1993). Since the
gene was isolated, the make up of the protein that it codes for has been
established. However, the exact function of that protein is still not understood.
The September 8, 1995, issue of Science documented how the Conaway team
located a substance called Elogin that is important in cell growth. Elogin
is made up of three small proteins (A, B and C). It is thought to play a
role in cell development and death. The VHL gene encodes for a specific
protein 213 amino acids long. However, to use this code it must first be
transcribed into RNA which is translated into Elogin. The transcription
process begins with an initiation and then continues with elongation. Elogin
plays a key role in elongation. The VHL protein binds to Elogin substrates
therefore inhibiting formation. The absence of Elogin blocks transcription
which stops the cell from dividing uncontrollably.
Everyone has two copies of the VHL gene. A mutation must occur in both copies
of the gene to stop production of the tumor suppresser protein encoded by
the gene. A person diagnosed with VHL has inherited the dysfunctional copy
of the gene from their affected parent. One gene intact is enough to produce
the needed tumor repressor. A person with one copy may develop tumors if
a mutation occurs that deactivates the one functional gene remaining. The
absence of the tumor repressor is only the first step in the formation of
tumors. A tumor needs to be initiated. The initiation is thought to be caused
by the same environmental factors that caused the VHL gene to mutate in
the first place.
The following is a case study of a family afflicted with the genetically
based Von Hippel-Lindau Disease.
The family diagrammed above have several members who have tumors. Arnold
died of kidney cancer and his son Elmer, as a child, developed a brain tumor
and eye tumor which were removed successfully. Annette, a mother of 4, died
at 42 of a pancreatic tumor. Von Hippel-Lindau Disease was suspected and
confirmed after genetic testing. Fay and Elmer had their children tested.
Their son Daryl had a small kidney tumor while Hannah was tumor free. Frank
and Annette allowed Jill and Gus to be checked because they were older and
asked to be but, would not allow the identical twins, Bill and Will.
The geneticist that diagnosed Annette with VHL enrolled the family in a
research project in which several restriction fragment length polymorphisms
(RFLPs) are traced in each member of the family. RFLP markers A, B, C, and
D are found near the VHL gene loci. Arnold, Elmer and Annette, who had tumors
have markers A and C, as do Daryl and Jill. Phil, Rhonda, Hannah and Gus
have RFLPs C and D
The case study shows how Von Hippel-Lindau Disease has been passed down
through three generations. The affected individual, Arnold had a 50% chance
of passing the mutated copy of the gene on to one of his four offspring.
Elmer and Annette inherited the VHL gene from their father, Arnold while
Phil and Rhonda did not. Annette married an unaffected individual and had
four children, Jill, Gus and the identical twins Bill and Will. Jill has
the gene and Gus does not. Bill at age 34 develops a tumor, while his twin
Will still show no signs of a tumor. Since both Bill and Will have almost
identical genetic makeups the difference in gene expression is due to the
incomplete penetrance of the disease. A mutation on the second copy of the
tumor suppressing gene (VHL) has not occurred in Will even though he does
carry the one mutated copy of the gene.
Elmer the son of Arnold like Annette inherited the VHL gene. Elmer married
Fay and had two children Daryl and Hannah. Daryl was found to have the VHL
disease. The research project that the families are enrolled in has determined
the RFLP marker A is linked to the VHL gene. This information will make
it easier to determine affected individuals through RFLP testing.
The research that is ongoing, with this and many other diseases, will help
unravel the mysteries of the genetic controls of a large number of genetically
based diseases that can be inherited, such as VHL and those that occur by
John Travis, "Von Hippel-Lindau Disease" Science 260:1235 May
Quibble, Kaolin et al., "Binding of the Von Hippel-Lindau Tumor Suppresser
Protein to Elogin B and C," Science September 8, 1995., 3pp
Aso, Lane Conaway and Conaway, "Elogin(SIII): A multisubunit Regulator
of Elongation by RNA Polymerase II" Science, 1439-1446.
"Hippel-Lindau gene product", Nature Medicine (August 1995), 1:822-826
M. Linehn, M. I. Lerman, B. Zbar., "Identification of the Von Hippel-Lindau
(VHL) gene: its role in renal cancer." JAMA 273:564-70 February 15,
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