New from the Laboratory of Immunobiology

One of the major goals of our research program has been to identify the changes in the gene (mutations) that produce VHL. We have identified mutations in 85/114 (75%) of VHL families. This area of mutation research has provided an enormous amount of new information about VHL. I will summarize this information in this article.

Perhaps the most striking observation is that there appear to be three types of von Hippel-Lindau disease. VHL type 1 is the commonest form of the disease and is characterized by a tendency to develop tumors in the eyes, brain, spinal cord, kidney and pancreas. VHL type 2 is less common. VHL type 2 differs from type 1 in that affected family members may develop pheochromocytomas. VHL type 2 is further divided into types 2A and 2B. Individuals in families with VHL type 2A develop pheochromocytomas, but not kidney cancer (this type of VHL is uncommon). Individuals in families with VHL type 2B develop pheochromocytomas and kidney cancer. (see Table 1)

Table 1: NCI classification of von Hippel-Lindau disease

This classification was based on studies of the mutations in a large number of VHL families. Families with more than 25 affected individuals were particularly useful in identifying what tumors occur and what tumors do not occur with particular mutations.

The spectrum of tumors that occur in a particular VHL family can be described as the phenotype.¹ One major result of our work is that we now know what types of tumors accompany particular VHL mutations. For example, a mutation at position 505 in the VHL gene that changes the DNA building block T to C is associated with VHL type 2A, that is eye, brain and adrenal tumors but not kidney or pancreatic tumors. For another example, a mutation at position 712 or 713 in the VHL gene that changes the DNA building block C to T, or G to A, is associated with VHL type 2B, that is eye, brain, kidney, adrenal and pancreas tumors. From the mutation in the VHL gene, one can make informed predictions as to which tumors will develop in a particular family. We are gathering together mutation data from families from research workers in the U.S., Great Britain, Europe and Japan. This information when combined with phenotype will be useful to investigators trying to predict disease manifestations.

One of the most striking observations to emerge from studies of mutations of the VHL gene involves the finding of exactly the same mutation in families that are not thought to be related. This situation can come about in two ways: (1) the mutation has occurred several times in the population; (2) the families with the identical mutation are in fact related, they have a distant common ancestor, but are unaware of this fact.

We have had examples of both situations in our studies. There are 14 families in Germany and 2 German families living in Pennsylvania that have the identical VHL mutation. The evidence suggests that these families have a common ancestor with a VHL mutation. There are families with VHL from several different countries that have the identical 712-713 mutation. The evidence suggests that this mutation developed independently in these populations.

This information is published in the December 14, 1994, issue of Human Mutation.

1. Phenotype: The entire physical makeup of an individual: hair, eye color, and in VHL, the types of tumors present in the family.

as published in the March 1995 issue of VHL Family Forum, 3:1

As published in the VHL Family Forum, 3:1, March 1995. For permission to reprint, please contact the VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.