Novel Homozygous Mutation of the Internal Translation Initiation Start Site ofVHLis Exclusively Associated with Erythrocytosis: Indications for Distinct Functional Roles of von Hippel-Lindau Tumor Suppressor Isoforms

Abstract

Congenital secondary erythrocytosis is a rare disorder characterized by increased red blood cell production. An important cause involves defects in the oxygen sensing pathway, in particular the PHD2-VHL-HIF axis. Mutations in VHL are also associated with the von Hippel-Lindau tumor predisposition syndrome. The differences in phenotypic expression of VHL mutations are poorly understood. We report on three patients with erythrocytosis, from two unrelated families. All patients show exceptionally high erythropoietin (EPO) levels, and are homozygous for a novel missense mutation in VHL: c.162G>C p.(Met54Ile). The c.162G>C mutation is the most upstream homozygous VHL mutation described so far in patients with erythrocytosis. It abolishes the internal translational start codon, which directs expression of VHLp19, resulting in the production of only VHLp30. The exceptionally high EPO levels and the absence of VHL-associated tumors in the patients suggest that VHLp19 has a role for regulating EPO levels that VHLp30 does not have, whereas VHLp30 is really the tumor suppressor isoform.

The Expression of VHL (Von Hippel-Lindau) After Traumatic Spinal Cord Injury and Its Role in Neuronal Apoptosis

“…This VHL protein encoded by the VHL gene is well known as an E3 ubiquitin [8]. It is widely accepted that the a-subunit of hypoxia-inducible factor(HIF-a) is the degradation target of VHL-containing E3 ligase in normal physiological conditions [13,14]. Moreover, the ligand stromal cell-derived factor (SDF)-1 and CXC chemokine receptor 4 (CXCR4) were also regarded as HIF targets, which suggests that HIF activation could lead to the potential metastasis of cancer cells [15,16].…”

Early‐onset and severe pulmonary arterial hypertension due to a novel compound heterozygous association of rare VHL mutations: A case report and review of existing data

“…Both our patient's VHL mutations have been separately linked to polycythemia and PAH. [3][4][5][6][7] However, our patient's combination of VHL mutations has never been reported so far. As mentioned above, our team previously reported the first documented case of PAH in a Moroccan Berber carrier of the homozygous c.162G>C (p.Met54Ile) mutation.…”

“…11 Elevated EPO level is one of the hallmarks of Chuvash polycythemia, an autosomal recessive disorder caused by the VHL mutation R200W, and very high EPO levels have been previously described in carriers of the p.Met54Ile and p.Asp126Asn mutations. [5][6][7]12 Also, organomegaly, including splenomegaly, has been previously reported in carriers of similar or other VHL mutations including the Chuvash mutation. 6,13 Extramedullary hematopoiesis occurring in the spleen has been shown in mice models of Chuvash polycythemia, which could explain the associated splenomegaly.…”

“… 7 It was also shown to segregate with erythrocytosis in two families. 7 Functional studies were performed for the c.376G>A (p.Asp126Asn) variant using VHL‐null renal carcinoma cells stably transfected to express this mutant. The study showed increased levels of HIF‐1α and increased expression of its target genes in mutant cells compared to wild‐type cells.…”

Advances in understanding the mechanisms of erythropoiesis in homeostasis and disease

“…Similar defects are observed in Egln1 ( Phd2 ) knockout mice, with no phenotype in heterozygotes suggesting a dominant negative effect of the human P317R and R371H mutations (Percy et al , ). A mutation in the downstream VHL gene, (R200W, M54I), encoding the VHL protein that recognizes hydroxylated HIFα and marks it for subsequent degradation, is associated with Chuvash polycythaemia (Kaelin, ; Bartels et al , ). The mutation lies within the HIF binding domain of VHL and in mice was shown to specifically disrupt HIF1β binding (Hickey et al , ).…”