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876 Part VI: The Erythrocyte Chapter 57: Primary and Secondary Erythrocytoses 877

Figure 57–3. Elongins B, C, and proteins Rbx1, Cul2 E2, and
NEDD 8 are interacting proteins that facilitate von Hippel-Lindau
(VHL) function. Interaction of mutated VHL protein with
HIF-1α. The Chuvash VHL mutation leads to the impaired inter-
action with HIF-1α, which results in impaired degradation in
26S proteasome and augmented hypoxia sensing. CP, Chuvash
polycythemia.

of genetic linkage to erythropoietin and EPOR loci, and no evidence patients were described in whom a null VHL allele was more rigorously
95
of abnormal hemoglobin. In a study of five multiplex Chuvash fam- excluded 101,102 ; the molecular mechanism of their polycythemic pheno-
ilies with Chuvash polycythemia, a homozygous mutation of the von type remains to be elucidated.
Hippel-Lindau (VHL) gene (598C>T); that is, VHL R200W , was found in To address the question of whether the VHL 598C>T substitution
all affected individuals. This mutation impairs the interaction of VHL occurred in a single founder or resulted from recurrent mutational
protein (pVHL) with both HIF-1α and HIF-2α, thus reducing the rate of events, haplotype analysis of eight highly informative single nucle-
ubiquitin-mediated destruction of HIF-1α and HIF-2α (Chap. 32). As a otide polymorphic markers covering 340 kb spanning the VHL gene
result, the level of HIF-1 and HIF-2 heterodimers increases and leads to was performed on 101 subjects bearing the VHL 598C>T mutation
the increased expression of target genes, including the erythropoietin and 447 normal unrelated individuals from Chuvash, Southeast Asian,
49
(EPO), vascular endothelial growth factor (VEGF), and plasminogen white, Hispanic, and African American ethnic groups. Polymorphism
4,5
activator inhibitor genes (PAI-1), among others. Figure 57–3 depicts of the VHL locus in normal controls (having a wild VHL 598C allele)
the effect of this mutation on hypoxic sensing. The role of circulating and subjects bearing Chuvash polycythemia VHL 598T were in strong
erythropoietin in the Chuvash polycythemia phenotype is indisput- linkage disequilibrium. These studies indicated that, in most individ-
able. However, there must be other factors associated with the Chuvash uals, the VHL 598C>T mutation arose in a single ancestor between
polycythemia VHL mutation that contribute to the polycythemic phe- 51,000 and 12,000 years ago. However, this is not the case for a Turkish
notype, as the erythroid progenitors of Chuvash polycythemia patients polycythemic family with a VHL 598C>T mutation wherein the VHL
are hypersensitive in vitro to extrinsic erythropoietin; the mechanism 598C>T mutation occurred independently. 102
of this observation is not fully explained. Some, but not all, patients Chuvash polycythemia homozygotes have decreased survival
4,5
with other VHL mutations have erythropoietin hypersensitive erythroid because of thrombotic and hemorrhagic complications, mostly in the
colonies 96–98 ; in these patients there is also increased expression of the venous circulation, and thus are under negative selection pressure.
99
RUNX1 and NFE1 genes, which can stimulate erythropoiesis. 6 The high frequency of the mutation in some areas may be the result of
Despite increased expression of HIF-1α, HIF-2α, and VEGF in random factors (“drift”), but it is also possible that propagation of the
normoxia, Chuvash polycythemia patients do not display a predisposi- VHL 598C>T mutation is the result of a survival advantage for hete-
tion to tumor formation. Imaging studies of 33 Chuvash polycythemia rozygotes. Such an advantage might be related to a subtle improvement
patients revealed unsuspected cerebral ischemic lesions in 45 percent, of iron metabolism, erythropoiesis, embryonic development, energy
106
but no tumors characteristic of VHL syndrome. There also, is a high metabolism, or some other as yet unknown effect. Indeed, heterozy-
99
52
prevalence of this disorder on the Italian island of Ischia. The Chuvash gotes were shown to be less likely to be anemic compared to control
VHL R200W mutation has also been described in whites in the United States subjects. Another potential protective role of a mildly augmented
107
and Europe, and in people of Punjabi/Bangladeshi Asian ancestry. hypoxic response is improved protection against bacterial infections, as
100
Some patients with congenital polycythemia have proved to be com- the hypoxia-mediated response has been reported to be essential for the
pound heterozygotes for the VHL R200W mutation and other VHL muta- bactericidal action of neutrophils. 108
tions. Additionally, two distantly related Croatians with polycythemia Classic von Hippel-Lindau Syndrome VHL syndrome is an auto-
are homozygous for VHL H191D , the first example of a homozygous VHL somal dominant genetic abnormality affecting the posttranslational
germline mutation other than VHL R200W causing polycythemia. 51,54,101–105 control of HIF-1α. 109–111 The syndrome is characterized by a propensity
A small number of cases of congenital polycythemia that appear to for developing renal cell carcinomas, retinal hemangioblastomas, cere-
have a mutation of only one VHL allele confound an obvious pathophys- bellar and spinal hemangioblastomas, pancreatic cysts, and pheochro-
iologic explanation. In a Ukrainian family, two children with polycythe- mocytomas. The tumors result from a somatic mutation in addition to
mia were heterozygotes for VHL 376G>T (D126Y), but the father with the germline mutation, that is, loss-of-heterozygosity. Polycythemia is
104
the same mutation was not polycythemic. An English polycythemic not part of VHL syndrome but hemangioblastomas of the central ner-
106
patient was a heterozygote for VHL 598C>T ; but the inheritance vous system, and, less commonly, pheochromocytoma and renal cancer,
of the deletion of a VHL allele, or null VHL allele, in a trans position have been associated with polycythemia mediated by paraneoplas-
111
was not excluded. Subsequently, two polycythemic VHL heterozygous tic erythropoietin production. Other patients with VHL syndrome

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