Comment on Perrotta et al, page 514
In this issue, Perrotta and colleagues from the Second University of Naples report on their finding of endemic congenital polycythemia due to homozygous VHL 598C>T on the Italian island of Ischia. The condition leads to increased expression of HIF-1, the master transcription factor of a growing list of genes under hypoxic control, and is associated with thrombosis, other vascular complications, and shortened life span. The article of Perrotta and colleagues underscores an important question: Is a slight augmentation of hypoxia sensing seen in heterozygotes for this inherited defect beneficial, providing some yet-to-be-elucidated survival advantage?
The genetic defect associated with congenital polycythemia in Ischia is identical to the mutation that causes augmented hypoxia sensing in Chuvash polycythemia, a condition first described in 1974 by the astute Russian clinical hematologist Lydia Polyakova. Dr Polyakova noted that polycythemia was endemic in the Chuvash people, an ethnic isolate in the Upper Volga region of Russia that migrated from Central Asia about 800 years ago, and refused to accept the false diagnosis of polycythemia vera that had been assigned to these patients. Instead, she carefully described the phenotype of the condition and studied the genetics using a self-taught knowledge of this discipline, a science forbidden by communist orthodoxy in the Soviet Union at the time. Dr Polyakova established the autosomal recessive inheritance of the disorder in her doctoral thesis, but the thesis was not accepted because of the inclusion of genetic methodology.
Chuvash polycythemia was hidden from Western knowledge and literature for more than 2 decades. In 2002, a team of Chuvash, Russian, and American investigators established the cause to be a homozygous germ-line mutation in the negative regulator of HIF-1 levels, the VHL gene (VHL 598C>T).2 While knowledge of the hypoxic control of genes originated from studies of erythropoietin transcriptional regulation, it soon became apparent that hypoxia-determined transcriptional control applies to critical genes of angiogenesis, energy metabolism, and iron metabolism, and plays crucial roles in embryonic development and in cancer genesis and progression.3 Soon after the molecular basis of Chuvash polycythemia was uncovered, the same mutation was reported sporadically in heterogeneous racial and ethnic groups.4 With one isolated exception in a Turkish family,5 the mutation was present on the same haplotype in all cases, indicating its origin from the same founder before human races diverged possibly about 50 000 years ago.4
This disorder in Ischia is now reported to have gene frequency even higher than in Chuvashia, with the astonishing rate of 14% heterozygosity of VHL 598C>T. The mutation is present on the same VHL haplotype as elsewhere.4,5 Much remains to be learned about the phenotype of this first congenital disorder of augmented hypoxic response, including the elucidation of the cause of the vascular and thrombotic defects and the surprising paucity of malignancies that frequently occur in the individuals with either somatic or germ-line and somatic mutations of VHL alleles. The unique spectrum of abnormalities associated with the VHL 598C>T mutation begs the question if the 5′ location of this mutation, the continuous augmentation of HIF-1 from embryogenesis in all tissues, or mechanisms yet to be defined may provide a heretofore unidentified environment of protection from cancerogenesis. Furthermore, the worldwide occurrence of this mutation that causes decreased survival in homozygotes must provide some type of survival advantage for heterozygotes. Perrotta and colleagues' identification of the high prevalence of this mutation provides a valuable opportunity to more completely delineate the phenotype and clinical consequences of augmented hypoxia sensing. We submit that the functional significance of the VHL 598C>T mutation and inherited hypoxia sensing in general can now be better and more quickly delineated by studying 2 populations of different racial backgrounds that live in distinct environments. The outcome of parallel studies in Chuvashia and Ischia could rapidly improve our understanding of the role of HIF in conditions such as innate immunity, thrombosis, cancerogenesis, and perhaps preeclampsia.5 ▪