VHL plays a role in regulating several key functions in the cell, binding with other proteins and marking them for degradation -- essentially serving as an "off" switch for the function of these other proteins. You have heard a great deal about VHL's role in regulating VEGF which causes the growth of new blood vessels. Even more important is its role in the detection of low oxygen levels (hypoxia), regulating HIF-1alpha (hypoxia-inducible factor), leading to increased production of HIF-controlled genes, including erythropoietin (Epo) a hormone which stimulates the production of red blood cells, VEGF, and many other proteins. Without sufficient Epo, you can become severely anemic. With too much Epo, you can have too many red blood cells, a condition which is called polycythemia. Some rare patients with VHL syndrome have polycythemia, which has been attributed to Epo production by a tumor.

In the Chuvash Republic, a mid-Volga region of European Russia, there is a relatively high concentration of polycythemia which was clearly seen to be hereditary. Recently the genetic cause was mapped to the short arm of chromosome 3, the VHL gene. This Chuvash Polycythemia (CP) behaves differently from other VHL mutations. The most striking difference is that you only get CP if you have two altered copies of the VHL gene.

In the VHL mutations we know as causing the tumor-causing condition we know as VHL disease, inheritance is dominant, meaning that you need only one altered copy of the VHL gene to have a predisposition for development of VHL disease. In fact, a fetus with two altered copies of the VHL gene will normally die in utero. But the CP mutation is in a position where one copy seems to cause no symptoms, and only when two CP mutations are inherited does the individual show signs of polycythemia. This is helping us understand the functional importance of the various parts of the gene. Its position is near one of the mutations currently associated with a VHL pheo family.

Map of the Russian Federation, showing tiny Chuvashia in the west

The Chuvash converted to Christianity, and were surrounded by peoples who embraced Islam. They kept to themselves, and rarely intermarried with the surrounding peoples, keeping the gene pool relatively distinct.

Among the Chuvash, the CP mutation is fairly common, leading researchers to wonder whether having one gene with the CP mutation has some beneficial effect. One copy of the sickle cell mutation, for example, protects that person from getting malaria, which in Africa is a very good thing. Two copies of the sickle cell mutation, however, cause sickle cell disease, which is a painful and crippling condition. But the beneficial effects of the single mutation are enough to ensure that this mutation will be preserved in the population.

VHL mutations have subsequently been found in a number of children with congenital polycythemia who are outside the Chuvash ethnic group: two Danish siblings, several US Caucasians, and two Pakistani and one Bangladesh families living in the U.K. Only one of these has any of the tumors normally associated with VHL disease. All are children, however, so it is possible that some VHL-related tumors may occur in later years. An ongoing epidemiological study of the Chuvash population has so far failed to identify an increased risk of VHL tumors. This may be due to other genetic or environmental factors such as carcinogen exposure or modifier genes. Learning more about these factors might also provide strategies for dealing with VHL disease.

About half the patients with apparent congenital polycythemia and increased serum Epo have VHL mutations. The multi-national research team headed by Dr. Josef Prchal at Baylor College of Medicine in Houston, Texas, now believes that "VHL mutations are the most frequent cause for congenital polycythemia and define a new class of polycythemic disorder, polycythemias due to augmented hypoxia sensing," as recently published in the American Journal of Human Genetics (Pastore et al, August 2003).

This team would appreciate the help and participation of any family with pheochromocytomas that also has a member with polycythemia, or whose VHL mutation has not yet been found. Please call Dr. Prchal or Dr. Pastore
directly, or call Joyce Graff to discuss this further.Dr. Prchal or Dr. Pastore:
+1(713)798-7520

Joyce Graff in the VHL Office:
+1 (617) 277-5667 or
1-800-767-4VHL, option 4
References: Y.D. Pastore et al., Mutations in the VHL gene in sporadic apparently congenital polycythemia, Blood (United States), Feb 15 2003, 101(4) p1591-5
S.O. Ang et al, "Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia", Nat Genet (United States), Dec 2002, 32(4) p614-21

Y.D. Pastore et al., "Mutations of von Hippel-Lindau tumor suppressor gene and congenital polycythemia," Am J Hum Genet (United States), Aug 2003, 73(2) p412-9

The Chuvash Republic [choo-väsh-ya] or Chuvashia, (1990 pop. 1,326,000), 7,066 sq. mi. (18,301 sq km), is a member state of the Russian Federation, in East central European Russia, in the middle Volga valley. Cheboksary is the capital. The region, consisting largely of the Chuvash plateau, is wooded steppe with some peat bogs. Grain, potatoes, flax, hemp, fruit, and sugar beets are grown, and livestock is raised. With about one third of the area in forests, both lumbering and woodworking are important occupations. Among the republic's other industries are oil and natural gas refining, metalworking, railway repair, and food and flax processing. The Trans-Siberian Railroad crosses the republic, and secondary lines from the main track service many towns. The Chuvash ethnic group makes up some 70% of the population and Russians (who are mostly urban) around 25%; there are Mordovian, Tatar, and Ukrainian minorities. The Chuvash, descendants of the medieval Bulgars, represent a mixture of Finnish and Mongolian peoples. They speak a Turkic language and adhere to Orthodox Christianity. Conquered by the Mongols in the 13th and 14th centuries, the Chuvash came under Russian rule in 1552. The Chuvash Autonomous Region was established in 1920; it became an autonomous republic in 1925. A revival of Chuvash culture began in 1968. Chuvashia was a signatory to the 1992 treaty that created the Russian Federation. It has a 200-member parliament.

Chuvashia is sometimes called the land of one hundred thousand embroideries and songs. Preserving national traditions, Chuvashes painstakingly protect their folklore and national crafts. Since olden times, Chuvash embroidery and woodcarving have been famous in the neighboring regions; this ancient trade has grown into a factory production, and nowadays art works receive recognition at international exhibitions, and are exported. The brilliant, beautiful dances of Chuvashes and their fine musical melodies affect the hearts of all those who see and hear them.Adapted from Chuvash Republic: Invitation to Cooperate, http://www.cap.ru/cap/main.asp?id=103 See also U.S.-Russia Business Council

As printed in the VHL Family Forum 11:3, September 2003. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org.