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Von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis.

ABSTRACT: The R200W mutation in the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL) is unique in that it is not associated with tumor development, but rather with Chuvash polycythemia, a heritable disease characterized by elevated hematocrit and increased serum levels of erythropoietin and VEGF. Previous studies have implicated hypoxia-inducible factor-1alpha (HIF-1alpha) signaling in this disorder, although the effects of this mutation on pVHL function are not fully understood. In order to explore the mechanisms underlying the development of this polycythemia, we generated mice homozygous for the R200W mutation (Vhl(R/R)). Vhl(R/R) mice developed polycythemia highly similar to the human disease. The activity of HIF proteins, specifically the HIF-2alpha isoform, was upregulated in ES cells and tissues from Vhl(R/R) mice. Furthermore, we observed a striking phenotype in Vhl(R/R) spleens, with greater numbers of erythroid progenitors and megakaryocytes and increased erythroid differentiation of Vhl(R/R) splenic cells in vitro. These findings suggest that enhanced expression of key HIF-2alpha genes promotes splenic erythropoiesis, resulting in the development of polycythemia in Vhl(R/R) mice. This mouse model is a faithful recapitulation of this VHL-associated syndrome and represents a useful tool for studying polycythemias and investigating potential therapeutics.

SUBMITTER: Hickey MM

PROVIDER: S-EPMC2066197 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice.

Project description:Mutation of the von Hippel-Lindau (VHL) tumor suppressor protein at codon 200 (R200W) is associated with a disease known as Chuvash polycythemia. In addition to polycythemia, Chuvash patients have pulmonary hypertension and increased respiratory rates, although the pathophysiological basis of these symptoms is unclear. Here we sought to address this issue by studying mice homozygous for the R200W Vhl mutation (VhlR/R mice) as a model for Chuvash disease. These mice developed pulmonary hypertension independently of polycythemia and enhanced normoxic respiration similar to Chuvash patients, further validating VhlR/R mice as a model for Chuvash disease. Lungs from VhlR/R mice exhibited pulmonary vascular remodeling, hemorrhage, edema, and macrophage infiltration, and lungs from older mice also exhibited fibrosis. HIF-2alpha activity was increased in lungs from VhlR/R mice, and heterozygosity for Hif2a, but not Hif1a, genetically suppressed both the polycythemia and pulmonary hypertension in the VhlR/R mice. Furthermore, Hif2a heterozygosity resulted in partial protection against vascular remodeling, hemorrhage, and edema, but not inflammation, in VhlR/R lungs, suggesting a selective role for HIF-2alpha in the pulmonary pathology and thereby providing insight into the mechanisms underlying pulmonary hypertension. These findings strongly support a dependency of the Chuvash phenotype on HIF-2alpha and suggest potential treatments for Chuvash patients.

| S-EPMC2827942 | biostudies-literature

Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia.

Project description:The von Hippel-Lindau (pVHL) protein plays an important role in hypoxia sensing. It binds to the hydroxylated hypoxia-inducible factor 1 alpha (HIF-1 alpha) and serves as a recognition component of an E3-ubiquitin ligase complex. In hypoxia or secondary to a mutated VHL gene, the nondegraded HIF-1 alpha forms a heterodimer with HIF-beta and leads to increased transcription of hypoxia-inducible genes, including erythropoietin (EPO). The autosomal dominant cancer-predisposition von Hippel-Lindau (VHL) syndrome is due to inheritance of a single mutated allele of VHL. In contrast, we recently showed that homozygous germline 598C-->T VHL mutation leads to Chuvash polycythemia (CP). We subsequently found VHL mutations in three unrelated individuals unaffected with CP, one of whom was compound heterozygous for the 598C-->T mutation and another VHL mutation. We now report seven additional polycythemic patients with VHL mutations in both alleles. Two Danish siblings and another American boy were homozygous for the VHL 598C-->T mutation. Three unrelated white Americans were compound heterozygotes for 598C-->T and another VHL mutation, 562C-->G in two and 574C-->T in the third. Additionally, a Croatian boy was homozygous for a 571C-->G VHL mutation, the first example of homozygous VHL germline mutation causing polycythemia, other than the VHL 598C-->T mutation. We have not observed VHL syndrome-associated tumors in polycythemic subjects or their heterozygous relatives; however, this will need to be evaluated by longitudinal studies. Over all, we found that up to half of the consecutive patients with apparent congenital polycythemia and increased serum Epo we have examined have mutations of both VHL alleles. Those findings, along with reports of CP, underscore that VHL mutations are the most frequent cause of congenital polycythemia and define a new class of polycythemic disorder, polycythemias due to augmented hypoxia sensing.

| S-EPMC1180379 | biostudies-literature

Hypoxia-inducible factor underlies von Hippel-Lindau disease stigmata.

Project description:von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that causes a predisposition to renal clear-cell carcinoma, hemangioblastoma, pheochromocytoma, and autosomal-recessive familial polycythemia. pVHL is the substrate conferring subunit of an E3 ubiquitin ligase complex that binds to the three hypoxia-inducible factor alpha subunits (HIF1-3α) for polyubiquitylation under conditions of normoxia, targeting them for immediate degradation by the proteasome. Certain mutations in pVHL have been determined to be causative of VHL disease through the disruption of HIFα degradation. However, it remains a focus of investigation and debate whether the disruption of HIFα degradation alone is sufficient to explain the complex genotype-phenotype relationship of VHL disease or whether the other lesser or yet characterized substrates and functions of pVHL impact the development of the VHL disease stigmata; the elucidation of which would have a significant ramification to the direction of research efforts and future management and care of VHL patients and for those manifesting sporadic counterparts of VHL disease. Here, we examine the current literature including the other emergent pseudohypoxic diseases and propose that the VHL disease-phenotypic spectrum could be explained solely by the varied disruption of HIFα signaling upon the loss or mutation in pVHL.

| S-EPMC9427099 | biostudies-literature

The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high-energy phosphate metabolism.

Project description:Hypoxia-inducible factor (HIF) appears to function as a global master regulator of cellular and systemic responses to hypoxia. HIF pathway manipulation is of therapeutic interest; however, global systemic upregulation of HIF may have as yet unknown effects on multiple processes. We used a mouse model of Chuvash polycythemia (CP), a rare genetic disorder that modestly increases expression of HIF target genes in normoxia, to understand what these effects might be within the heart. An integrated in and ex vivo approach was employed. Compared with wild-type controls, CP mice had evidence (using in vivo magnetic resonance imaging) of pulmonary hypertension, right ventricular hypertrophy, and increased left ventricular ejection fraction. Glycolytic flux (measured using [(3)H]glucose) in the isolated contracting perfused CP heart was 1.8-fold higher. Net lactate efflux was 1.5-fold higher. Furthermore, in vivo (13)C-magnetic resonance spectroscopy (MRS) of hyperpolarized [(13)C1]pyruvate revealed a twofold increase in real-time flux through lactate dehydrogenase in the CP hearts and a 1.6-fold increase through pyruvate dehydrogenase. (31)P-MRS of perfused CP hearts under increased workload (isoproterenol infusion) demonstrated increased depletion of phosphocreatine relative to ATP. Intriguingly, no changes in cardiac gene expression were detected. In summary, a modest systemic dysregulation of the HIF pathway resulted in clear alterations in cardiac metabolism and energetics. However, in contrast to studies generating high HIF levels within the heart, the CP mice showed neither the predicted changes in gene expression nor any degree of LV impairment. We conclude that the effects of manipulating HIF on the heart are dose dependent.

| S-EPMC5142182 | biostudies-literature

Von Hippel-Lindau Disease.

Project description:Von Hippel-Lindau disease is an autosomal dominant syndrome which occurs secondary to germline mutations in the VHL tumor suppressor gene, located on chromosome 3. Clinically von Hippel-Lindau disease is characterized by an increased risk of developing simple visceral cysts, most commonly in the pancreas and kidneys, in addition to an increased risk of developing neoplasms, often with clear cell features, in a multitude of organ systems. The most common neoplasms are cerebellar and retinal hemangioblastomas, adrenal pheochromocytomas, clear cell renal cell carcinomas, pancreatic neuroendocrine tumors, pancreatic serous cystadenomas, and endolymphatic sac tumors. These lesions most commonly present during adulthood; however, screening and surveillance for the development of these lesions should begin in the pediatric years for patients with von Hippel-Lindau disease. In this review article, the genetics and most common neoplasms of von Hippel-Lindau disease are reviewed, with an eye towards implications for the pediatric patient.

| S-EPMC4918695 | biostudies-literature

Von hippel-lindau disease.

Project description:A germline mutation in the Von-Hippel Lindau (VHL) gene predisposes carriers to development of abundantly vascularised tumours in the retina, cerebellum, spine, kidney, adrenal gland and pancreas. Most VHL patients die from the consequences of cerebellar haemangioblastoma or renal cell carcinoma. The VHL gene is a tumour suppressor gene and is involved in angiogenesis by regulation of the activity of hypoxia-inducible factor 1-alpha (HIF1-alpha). Clinical diagnosis of VHL can be confirmed by molecular genetic analysis of the VHL gene, which is informative in virtually all VHL families. A patient with (suspicion for) VHL is an indication for genetic counselling and periodical examination.

| S-EPMC2837060 | biostudies-literature

rs779805 Von Hippel-Lindau Gene Polymorphism Induced/Related Polycythemia Entity, Clinical Features, Cancer Association, and Familiar Characteristics.

Project description:Increased red blood cell count may result from primary erythrocytosis (polycythemia vera), but it is often due to secondary causes with increased erythropoietin levels. Secondary erythrocytosis may also be congenital due to different gene mutations of hemoglobin, hemoglobin stabilization proteins, EPO receptors, or oxygen sensing pathways. Von Hippel- Lindau gene mutation causes altered tissue oxygen sensation in VHL disease, usually with normal hemoglobin. Germline VHL mutations associate with classical VHL disease and represent genetic susceptibility for pheochromocytoma. VHL polymorphisms are mostly considered an innocent phenomenon. Still, some data indicate that these polymorphisms are not always harmless and can occur with prostate, renal, and colon cancer or even with isolated erythrocytosis. Seventy-eight patients referred to our department with elevated hemoglobin were screened for VHL mutations. There were no classical somatic VHL mutations. However, we found heterozygous (GA) or homozygous (AA) rs779805 VHL c.-195G>A polymorphism accompanied by erythrocytosis. These patients are Jak-2 negative, with normal or elevated EPO levels, sometimes with family accumulations and often phlebotomy needs, and in some cases with malignancies in the family. No other cause of erythrocytosis was found. We use phlebotomy regularly, and for those with cardiovascular risk factors, we recommend aspirin.

| S-EPMC8660678 | biostudies-literature

Von Hippel-Lindau Disease and the Eye.

Project description:Retinal hemangioblastoma (also referred to as retinal capillary hemangioma) is a benign lesion originating from the endothelial and glial components of the neurosensory retina and optic nerve head. Historically known as a manifestation of the von Hippel-Lindau (VHL) disease, it can be seen as an isolated finding or in association with some rare ocular conditions. In addition to characteristic ophthalmoscopic features, results of numerous ancillary tests including angiography, ultrasound, optical coherence tomography, and genetic tests may support the diagnosis and differentiate it from similar conditions. Because of serious life-threatening complications of VHL disease, every ocular approach to retinal hemangioblastomas should be in relationship with additional multidisciplinary diagnostic and therapeutic efforts. In addition, any patient with actual or probable diagnosis of VHL disease should be screened for ocular involvement. Unfavorable visual loss can occur early, and ocular complications of VHL range from exudative retinopathy to tractional retinal detachment, neovascular glaucoma, and phthisis bulbi. Accordingly, various treatment methods have been tested with overall acceptable responses, including photocoagulation, cryotherapy, photodynamic therapy, plaque radiotherapy, vitrectomy, and more novel intravitreal injections of anti-vascular endothelial growth factors and propranolol.

| S-EPMC7001024 | biostudies-literature

A Review of Von Hippel-Lindau Syndrome.

Project description:Von Hippel-Lindau syndrome (VHL) is a familial neoplastic condition seen in approximately 1 in 36,000 live births. It is caused by germline mutations of the tumor suppressor gene VHL, located on the short arm of chromosome 3. While the majority of the affected individuals have a positive family history, up to 20% of cases arise from de novo mutations. VHL syndrome is characterized by the presence of benign and malignant tumors affecting the central nervous system, kidneys, adrenals, pancreas, and reproductive organs. Common manifestations include hemangioblastomas of the brain, spinal cord, and retina; pheochromocytoma and paraganglioma; renal cell carcinoma; pancreatic cysts and neuroendocrine tumors; and endolymphatic sac tumors. Diagnosis of VHL is prompted by clinical suspicion and confirmed by molecular testing. Management of VHL patients is complex and multidisciplinary. Routine genetic testing and surveillance using various diagnostic techniques are used to help monitor disease progression and implement treatment options. Despite recent advances in clinical diagnosis and management, life expectancy for VHL patients remains low at 40-52 years. This article provides an overview of the major clinical, histological, and radiological findings, as well as treatment modalities.

| S-EPMC5541202 | biostudies-other

Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha gain-of-function mutation.

Project description:The hypoxia-inducible factors (HIFs; isoforms HIF-1?, HIF-2?, HIF-3?) mediate many responses to hypoxia. Their regulation is principally by oxygen-dependent degradation, which is initiated by hydroxylation of specific proline residues followed by binding of von Hippel-Lindau (VHL) protein. Chuvash polycythemia is a disorder with elevated HIF. It arises through germline homozygosity for hypomorphic VHL alleles and has a phenotype of hematological, cardiopulmonary, and metabolic abnormalities. This study explores the phenotype of two other HIF pathway diseases: classic VHL disease and HIF-2? gain-of-function mutation. No cardiopulmonary abnormalities were detected in classic VHL disease. HIF-2? gain-of-function mutations were associated with pulmonary hypertension, increased cardiac output, increased heart rate, and increased pulmonary ventilation relative to metabolism. Comparison of the HIF-2? gain-of-function responses with data from studies of Chuvash polycythemia suggested that other aspects of the Chuvash phenotype were diminished or absent. In classic VHL disease, patients are germline heterozygous for mutations in VHL, and the present results suggest that a single wild-type allele for VHL is sufficient to maintain normal cardiopulmonary function. The HIF-2? gain-of-function phenotype may be more limited than the Chuvash phenotype either because HIF-1? is not elevated in the former condition, or because other HIF-independent functions of VHL are perturbed in Chuvash polycythemia.

| S-EPMC3159892 | biostudies-other

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