Mutations in the VHL Gene Are the Major Identified Cause of Inherited Erythrocytosis.
Authors: Percy Melanie J. , Jones F. G.C. , Lappin T. R.J. , McMullin M. F. 
Published: April 2020

Abstract
The molecular basis of inherited erythrocytosis in most patients remains to be defined. Although all such patients have an absolute increase in red cell mass, their erythropoietin (EPO) levels differ widely, so they constitute a heterogeneous group of disorders known collectively as idiopathic erythrocytosis (IE). A proportion of individuals with IE progress to polycythemia vera (PV), a clonal disorder arising from a multipotent progenitor. Recently a gain-of-function mutation in Janus kinase 2 (JAK2), V617F, has been described in myeloproliferative disorders (MPD) and a stream of publications has confirmed its presence in the majority of patients with PV. Screening IE patients for this mutation will provide a useful additional means for delineating inherited and clonal disorders of erythrocytosis. Over the last decade we have maintained a registry of British and Irish erythrocytosis patients, consisting of clinical information and DNA samples obtained following full ethical approval. Screening the EPO receptor (EPO-R) in 120 patients identified one patient with a G6002A mutation, which leads to truncation of the receptor by 70 amino acids, increased sensitivity to EPO, and erythrocytosis. Screening the same patients for mutations in the von Hippel Lindau (VHL) gene has revealed individuals from 8 families of Asian origin who are homozygous for the Chuvash (R200W) mutation causing erythrocytosis. In addition, one Caucasian individual of English descent is compound heterozygous for R200W and the recently described G144R VHL mutation. A further individual, D1 (Percy et al, 2003Blood102:1097), of the same ethnicity is heterozygous for the Chuvash mutation and has been found to express the wild type allele. Both his mother and son, who are heterozygous for the Chuvash mutation, do not have IE, suggesting that the patient harbors a second unidentified genetic defect. Several such individuals have already been described (reviewed by Randi et al, 2005 Haematologica 90:689). In order to estimate the proportion of IE patients likely to progress to PV, 65 individuals from the registry with EPO levels in the low to normal range were screened by amplification refractory mutation system (ARMS) PCR for the MPD-associated V617F JAK2 mutation. Two individuals were positive, one of whom subsequently proceeded rapidly to PV, while the other has remained stable without any disease progression. In addition 9 families with VHL mutations were also screened and all were found to be negative for the JAK2 mutation, suggesting that the occurrence of these mutations tends to be mutually exclusive. Also the V617F JAK2 mutation does not constitute the second genetic defect in patient D1 who is heterozygous for the Chuvash VHL mutation. Although VHL mutations are the most frequent cause of inherited erythrocytosis in our registry they are present in only ~10% of patients, while the gain-of-function of JAK2 mutation is rare, leaving ~90% of the IE cases unexplained. Further study of this group may reveal additional regulatory mechanisms involved in red cell homeostasis.