von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome passed down in an autosomal-dominant fashion. It is named after physicians Eugen von Hippel and Arvid Lindau, who first described families with a genetic predisposition to retinal and central nervous system (CNS) hemangioblastoma, respectively (Lindau, 1904; Davison et al., 1936; Hippel, 1904). VHL disease is rare, afflicting approximately 1 in 35,000 people (Neumann and Wiestler, 1991; Maher et al., 1991). In addition to the retinal and central nervous system hemangioblastoma, other cardinal features of VHL disease include clear-cell renal cell carcinoma (RCC), the commonest form of kidney cancer, and pheochromocytoma, a neuroendocrine tumor derived from adrenal chromaffin cells, in addition to pancreatic, renal and epididymal cysts, endolymphatic sac tumors, and polycythemia (Lindau, 1904 ; Davison et al., 1936; Hippel, 1904).

In 1993, the VHL gene was cloned and mutations of the locus were determined to be causative of VHL disease (Latif et al., 1993). By sequencing the VHL gene in various families afflicted with VHL disease, a complex genotype-phenotype correlation emerged. First, VHL disease is broadly separated into two types based on the propensity of developing pheochromocytoma where Type 1 patients have a low risk while Type 2 patients have a high risk of pheochromocytoma. Type 1 patients also develop hemangioblastoma and RCC. Type 2 disease is further stratified into Type 2a (high risk of hemangioblastoma with low risk of RCC), Type 2b (high risk of hemangioblastoma and RCC), and Type 2c (only pheochromocytoma without the other disease manifestations). Moreover, VHL mutations have been found to be causative of autosomal-recessive familial polycythemia, which is sometimes referred to as Type 3 VHL disease (Table 1). While polycythemia refers to a nonspecific increase in the volume percentage of red blood cells in the blood, also known as hematocrit, this increase in VHL disease and other pseudohypoxic diseases is known to result from excess red blood cell production, termed erythrocytosis. VHL disease Type 1 and 2 are inherited in an autosomal-dominant manner, which predisposes an individual to developing cancer upon the loss of the remaining wild-type allele. In other words, there must be a loss of heterozygosity resulting either from large deletions, mitotic recombination, or hypermethylation of the wild-type allele in a susceptible cell for a tumor to form (Prowse et al., 1997). However, to develop polycythemia associated with VHL disease Type 3, an individual must inherit two mutated VHL alleles, meaning it is an autosomal-recessive disease.

The protein product of VHL is termed pVHL, which forms an E3 ubiquitin ligase complex (pVHL-E3) with elongin B, elongin C, cullin 2, and Rbx1 (Kamura et al., 1999; Cardote et al., 2017). pVHL serves as the substrate-conferring component of the pVHL-E3 ligase, an integral component in the metazoan oxygen-sensing pathway (Figure 1). The best-characterized substrates of the pVHL-E3 ligase remain the hypoxia-inducible factor (HIF) alpha subunit paralogs HIF1α, HIF2α, and HIF3α. HIFs are heterodimeric transcription factors consisting of an oxygen-labile α subunit and a constitutively expressed β subunit (Figure 1). In the presence of sufficient oxygen, prolyl hydroxylase (PHD) enzymes hydroxylate the conserved proline residues on HIFα, which results in pVHL binding to HIFα and subsequent polyubiquitylation leading to 26 S proteasomal-mediated degradation of HIFα (Figure 1; Epstein et al., 2001; Jaakkola et al., 2001; Ivan et al., 2001; Bruick and McKnight, 2001). Under hypoxic conditions, HIFα remains unhydroxylated, escapes recognition via pVHL, and is therefore not degraded. This pool of stabilized HIFα is able to both dimerize with HIFβ and translocate to the nucleus where it transcriptionally regulates many genes involved in the adaptive hypoxic response including metabolic enzymes, erythropoietin (EPO), and vascular endothelial growth factor (VEGF) (Figure 1; Jiang et al., 1996).

Figure 1

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Although the connection between HIF deregulation and VHL disease was readily appreciated, a hypothesis emerged that the complicated genotype-phenotype correlation in VHL disease could not be fully explained by HIF dysregulation alone. This argument implies that pVHL carries out other cellular functions and/or targets other substrates for ubiquitin-mediated degradation that are integral to the manifestation of the full spectrum VHL disease phenotypes. Here, we revisit the available and emerging evidence surrounding the relationship between HIF and VHL disease and propose that HIF dysregulation is the driver of the genotype-phenotype correlation in VHL disease.

The strongest evidence for additional non-HIFα related functions came from early biochemical studies of Type 2c pVHL mutants. Type 2c VHL disease is associated with pheochromocytoma without other disease phenotypes, and several Type 2c pVHL mutants were found to promote HIFα polyubiquitylation at seemingly wild-type levels (Hoffman et al., 2001; Clifford et al., 2001). A second peculiarity centered on Type 1 VHL disease. Despite Type 1 disease driven by mutations predicted to profoundly inactivate pVHL, including nonsense, frameshift and splicing mutations, these patients do not develop pheochromocytoma (Stebbins et al., 1999; Chen et al., 1995; Crossey et al., 1995; Stolle et al., 1998). Thus, pheochromocytoma seemed uncoupled from HIF stabilization (more on this later).

To better understand VHL disease, researchers searched for other targets and/or functions of pVHL. Notably, pVHL has been linked to the regulation of extracellular matrix proteins collagen and fibronectin (Ohh et al., 1998; Kurban et al., 1998a; Grosfeld et al., 2007; Stickle et al., 2004; Kurban et al., 1998b), microtubules (Thoma et al., 2009; Hergovich et al., 2006; Hergovich et al., 2003), primary cilia (Montani et al., 2010; Esteban et al., 2006), NFκB (Cummins et al., 2006; Yang et al., 2007), Human Antigen R (HuR) (Danilin et al., 2009; Massfelder et al., 2004), AKT kinase (Guo et al., 2016), p14/ARF (Minervini et al., 2015; Lai et al., 2011), and ZHX2 (Zhang et al., 2018).

A subset of these potential pVHL regulatory targets, including AKT, are proposed to interact with pVHL in a hydroxylproline-dependent manner following PHD-mediated hydroxylation. Notably, a systemic attempt to detect PHD-mediated hydroxylation of 24 non-HIFα substrates failed to reproduce and confirm previously published findings (Cockman et al., 2019). Further, a list of potential pVHL substrates, including fibronectin, collagen, tubulin, HuR, and p14/ARF, have been identified as pVHL interactors in high throughput studies with additional low-throughput supporting evidence in the BioGRID database (Oughtred et al., 2021). Each of these potential interactors, however, have only been identified in a single high-throughput experiment and all but HuR have been identified by the same high-throughput study (Lai et al., 2011; Oughtred et al., 2021). In contrast, the HIFα substrates of pVHL have been identified by numerous high-throughput and low throughput studies (143 identify HIF1α and 19 identify HIF2α in the BioGRID database) demonstrating a disparity in the confidence of the interactions (Oughtred et al., 2021). Thus, strong evidence of non-HIFα related bona fide biological functions of pVHL remains lacking.

Evidence for a HIF-centric model of VHL disease

Clinical evidence

Since the association of pVHL mutations with VHL disease, clinicians noted that largely unique groups of pVHL mutations were associated with the different types of VHL disease. It has been generally accepted that mutations that more markedly impact the ability of pVHL to degrade HIFα result in more ‘severe’ VHL disease phenotypes. Patients with large deletion and frameshift mutations generally develop Type 1 VHL disease, while patients with missense mutations develop Type 2 disease (Chen et al., 1995; Stolle et al., 1998; Maher et al., 1996). This concept can be further extrapolated to explain the heterogeneity of phenotypes within Type 2 VHL disease. Type 2c pVHL mutants, for example, cause exclusively pheochromocytoma and have been shown to degrade HIFα nearly as well as wild-type pVHL (Hoffman et al., 2001). Further, some pVHL mutations are associated with incomplete phenotypic penetrance, which has even been observed among members of the same VHL disease family. Thus, we propose that the various clinical phenotypes associated with VHL disease require different ‘doses’ of HIF. From polycythemia to pheochromocytoma to hemangioma/hemangioblastoma to RCC, a greater dose of HIF is required for disease onset. Inter-family heterogeneity among VHL disease patients reflects a differential loss of pVHL function — a mutation that completely abrogates the ability of pVHL to negatively regulate HIF leads to a greater HIF dose and more severe phenotype than mutations that only mildly impair pVHL function. Lastly, observed intra-family heterogeneity supports the idea that different phenotypes associated with VHL disease exist on a gradient of increasing HIF dose. Some individuals in a family, due to environmental, metabolic, and/or genetic factors, experience greater stabilization of HIF than other relatives with the same mutation, which leads to the development of phenotypes otherwise associated with greater loss of pVHL function (Figure 2).

Figure 2

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pVHL Y98 and Y112 are recognized as residues of interest as different missense mutations at these sites can elicit drastically different phenotypes. Both the Y98H and Y112H VHL mutations are classically associated with VHL Type 2a disease with a high penetrance of pheochromocytoma, but while the Y112H mutation appears to result in hemangioma/hemangioblastoma in only 20% of cases, the Y98H mutation displays a greater penetrance at ~50% (Brauch et al., 1995; Chen et al., 1996). This observation is also consistent with the fact that patients with the Y98H pVHL mutation are diagnosed earlier (mean of 19.7 years-old) than patients with the Y112H pVHL mutation (28.8 years-old) (Nielsen et al., 2011a). The fact that hemangioma/ hemangioblastoma penetrance lags behind pheochromocytoma penetrance in VHL disease patients with the Y112H mutation points to the idea of a gradient, where only a subset of these Type 2a patients develop the cardinal feature of vascular hemangioma/hemangioblastoma tumors.

In addition, a small number of patients with Type 2a pVHL mutants also develop RCC. Indeed, Type 2a VHL disease is classically defined as a ‘low’ chance of RCC rather than ‘no’ chance. A study of 16 families harboring the Y98H mutation found that some affected individuals exhibited symptoms consistent with Type 1 or 2b VHL disease. Out of 116 affected family members, 73 developed pheochromocytoma while 4 developed RCC (Brauch et al., 1995). Two individuals developed RCC in addition to pheochromocytoma (Type 2b) and two solely developed RCC (Type 1). Similarly, ~3% of individuals with the Y112H mutations also develop RCC (Nielsen et al., 2011b). In comparison, in a family harboring Y112N, 7 individuals developed RCC and only one developed pheochromocytoma, suggesting Y112N presents more commonly as Type 1 VHL disease (Bradley et al., 1999).

While Type 2c VHL disease is associated with pheochromocytoma, Type 2c mutations can sometimes ‘spillover’ and also cause hemangioma/hemangioblastoma. One example is the classic Type 2c VHL mutant V84L, which is associated solely with pheochromocytoma in most patients but in some cases, vascular tumors, including the possibility of spinal hemangioblastoma, and renal cysts are observed (Abbott et al., 2006). Similarly, the Type 2c VHL mutant G93S was linked with pheochromocytoma across multiple generations in a family with VHL disease, but further diagnostic workup revealed two retinal angiomas in the index patient and bilateral renal cysts in the index patient’s father (Schreinemakers et al., 2007). While renal cysts can be found in a population not carrying pVHL mutations, it is important to note that this could be evidence of progression of Type 2c VHL disease as individuals age.

As mentioned above, Type 2c VHL disease has perplexed the field as Type 2c pVHL mutants appear to regulate HIFα in a manner similar to wild-type pVHL, which would suggest that pheochromocytoma is uncoupled from HIFα degradation (Hoffman et al., 2001; Clifford et al., 2001). For example, a patient with bilateral pheochromocytoma and no other VHL-related symptoms was found to harbor a Y175C VHL mutation. When compared to wild-type pVHL, Y175C pVHL was able to degrade HIF efficiently under normoxic conditions (Astapova et al., 2018). But while in vitro studies failed to associate pheochromocytoma pathogenesis with HIF stabilization in the context of VHL disease, clinically observed EPAS1 (encodes HIF2α) and EGLN1 (encodes PHD2) mutations that result in HIF2α stabilization are now known to cause disease phenotypes that partially overlap with the VHL disease spectrum. Of particular interest, pheochromocytoma carcinogenesis is clinically associated with PHD2 loss-of-function mutations and HIF2α gain-of-function mutations in addition to pVHL loss-of-function mutations (Gardie et al., 2014; Ladroue et al., 2008; Därr et al., 2016; Taieb et al., 2016; Tarade et al., 2018). Therefore, it is possible that previous experiments suggesting the near wild-type activity of Type 2 c pVHL mutants lacked the sensitivity to assess differences in HIFα stabilization relative to wild-type pVHL that are biologically relevant. It is also possible that there is a more complex interplay between the relative stabilization of the different HIFα paralogs, which may be differentially affected by certain pVHL mutations.

HIF2-driven disease is particularly interesting because like VHL disease, it also presents as a gradient with escalating phenotypes comparable to Type 3, Type 2c, and even Type 2a VHL disease. Patients with mutations in EPAS1, the gene encoding HIF2α, have been reported to develop polycythemia and neuroendocrine tumors in dozens of patients (Därr et al., 2016; Taieb et al., 2016; Tarade et al., 2018). HIF2-driven disease can be segregated into two broad classes: Class 1 characterized by the presence of pheochromocytoma and/or paraganglioma (PPGL) with or without polycythemia, and Class 2 in which patients present solely with polycythemia (Tarade et al., 2018). Class 1 is further divided into three sub-classes where Class 1a presents with PPGL, somatostatinoma, and polycythemia, Class 1b presents with PPGL and polycythemia, and Class 1c presents with PPGL exclusively (Table 2). More rarely, patients with gain-of-function HIF2α mutations also present with hemangiomas and hemangioblastoma. While there is only a single case of hemangioblastoma linked to a HIF2α gain-of-function mutation, a unique and uncharacterized double F374Y and Q561K missense mutation, (Taieb et al., 2016) the clinical literature includes three reports of patients with HIF2-driven disease developing hemangiomas of the retina, liver, and cranial vault (Pacak et al., 2013; Dmitriev et al., 2020; Buffet et al., 2014). All three of these patients also developed polycythemia and pheochromocytoma/paraganglioma and were determined to have a HIF2α gain-of-function mutation otherwise associated with a complete penetrance of PPGL. While there is less clinical evidence of HIF2α driving hemangioma, relative to PPGL, liver hemangiomas associated with loss-of-pVHL mouse models can be rescued by co-deletion of HIF2α or HIFβ, which provides further evidence for the gatekeeping role of HIF2α in hemangioma and hemangioblastoma (Rankin et al., 2008; Rankin et al., 2005). Much like Type 2c VHL disease, Class 1a/b HIF2-driven disease can sometimes ‘spillover’ and trigger the formation of vascular hemangioma tumors. The remarkable fact that HIF2α gain-of-function mutations can phenocopy Type 2a VHL disease provides strong evidence for the role of HIF2α in Type 2c VHL disease. Not only do some canonical Type 2c VHL mutations also cause hemangiomas, a phenotype strongly linked with HIF2α signaling in Type 2a VHL disease, some VHL disease patients concurrently develop polycythemia, pheochromocytoma, and somatostatinoma, which matches the phenotypic profile of Class 1a HIF2-driven disease (Karasawa et al., 2001).

Table 2

HIF2-driven disease
	Class 1A	Class 1B	Class 1C	Class 2
PPGL	+	+	+	-
Somatostatinoma	+	-	-	-
Polycythemia	+	+	-	+

PHD2 mutations have been widely found to cause polycythemia. More rarely, PHD2 mutations, like PHD2 H374R and PHD2 A228S, trigger development of pheochromocytoma and/or paraganglioma (PPGL) in addition to polycythemia (Gardie et al., 2014; Ladroue et al., 2008; Yang et al., 2015). The patient harboring the H374R mutant originally presented with erythrocytosis, but a tumor matching the characteristics of a paraganglioma was later diagnosis at 43 years old (Ladroue et al., 2008) This individual displayed loss of the remaining wild-type EGLN1 allele. This observed loss of heterozygosity suggests that PHD2 plays a tumor suppressor role in chromaffin cells and the closely related paraganglia cells that are transformed in paraganglioma. Other reports of PHD2 mutation in polycythemia note that patients inherit a single mutated allele (Percy et al., 2006; Percy et al., 2007; Barradas et al., 2018). This could imply that haploinsufficiency of wild-type PHD2 might be enough to induce symptoms. Indeed, deletion of a single PHD2 allele or knock-in of a single mutant PHD2 allele in mice successfully recapitulates polycythemia, which was also found to be dependent on HIF2α (Arsenault et al., 2013). These cases also suggest mutations of EGLN1 may have a limited phenotypic range compared to VHL and HIF2-driven disease. The loss of PHD2 function may be compensated for by the other PHD paralogs, PHD1 and PHD3, preventing most instances of tumor formation but not all. Indeed, there has been one documented case of a disease-causing PHD1 mutation. This mutant, S61R, induced erythrocytosis development by age 6 and recurrent PPGL at age 14 (Yang et al., 2015).

There have also been documented cases of pVHL mutant-induced polycythemia (Type 3 VHL disease). R200W and H191D have both been identified as autosomal-recessive pVHL mutations that cause polycythemia (Pastore et al., 2003; Ang et al., 2002). And similarly to the role of HIF2α in liver hemangioma pathogenesis in loss-of-pVHL mouse models, inhibition of HIF2α rescues polycythemia in mouse models of polycythemia driven by the R200W mutation (Ghosh et al., 2021; Hickey et al., 2007; Ghosh et al., 2018).

While pVHL induced polycythemia is generally inherited in an autosomal-recessive manner, a study investigating eight children with polycythemia revealed one case in which a family harbored a heterozygous VHL mutant inducing a phenotype. Two siblings in the family were found to be heterozygous for D126Y and had increased levels of hematocrit and erythropoietin. One of the siblings had a history of tumors, developing a pulmonary angioma at age 10 and a renal subcapsular hemangioma at age 15. This would indicate that pVHL D126Y straddles the line between Type 3 and Type 2a disease. All the patients in this study were young (10–19 years old; Pastore et al., 2003); therefore, it remains unclear whether these patients will develop tumors later in life.

Just like VHL disease, HIF2α and PHD2 mutations can present a wide range of phenotypes where mutations that most stabilize HIF2α cause the worst phenotypes (more on this later). Thus, mutations in these three separate components of the HIFα-degradation pathway — substrate (HIF2α), hydroxylase (PHD2), and E3 ubiquitin ligase (pVHL) — all present with similar phenotypes. The common factor in the disruption of these three components of the pathway is the ultimate stabilization of HIFα, in particular HIF2α, and the correlation between the severity of disease and the degree of disruption to the HIFα degradation pathway naturally suggest that the causative factor is HIFα (Figure 2).

Fully elucidating molecular mechanism underlying VHL disease remains difficult given a dearth of relevant culture and animal models. VHL-null kidney cancer cell lines led to the discovery of the role of pVHL and prolyl hydroxylases in negatively regulating HIF, but overexpression of mutant pVHL, PHD2, or HIF2α remains a blunt tool that is not well-suited for differentiating different disease classes. Without a cell culture system relevant to the RCC, hemangioma or PPGL carcinogenesis process, the principal readout available is overall stabilization of HIF2α, a decidedly qualitative result. Thus, the study of pseudohypoxic disease, which benefits greatly from rich clinical data, requires a model for the one-to-one comparison of pVHL, HIF2α, and PHD2 mutants. If our HIF-centric model of pseudohypoxic disease holds then we would expect that Type 2c pVHL mutants would result in similar HIF2α stabilization as Class 1 HIF2α mutants or cancer-causing PHD2 mutants; Type 2a pVHL mutants would result in greater stabilization of HIF2α than either Type 2c pVHL mutants or Class HIF2α mutants; and Type 2b pVHL mutants would result in even greater stabilization of HIF2α.

Any model developed to assess the HIF-centric model of VHL disease, where increasing dysregulation of HIF corresponds to a wider range of phenotypes, will need to be able to assess overall HIF stabilization in a system that includes all components of the PHD-pVHL-HIF axis. Further, these components will need to reflect physiologically relevant concentrations. Lastly, quantitative readouts directly related to the stabilization of HIF2α and/or HIF1α would be required.

Although possible to recapitulate the PHD-pVHL-HIF axis in living systems, the ability to introduce disease-causing mutations without over-expressing one component is limited. CRISPR-mediated gene editing of endogenous VHL, EGLN1, or EPAS1 loci remains one possibility to directly compare the impact of disease-causing mutations on the regulation of cellular HIF pools. By comparing this cellular data with known clinical phenotypes, the HIF-centric model could be directly addressed.

Further, there is some limited success in recapitulating pseudohypoxic disease phenotypes in mice (Rankin et al., 2005; Hickey et al., 2007; Wang et al., 2019; Tan et al., 2013). Generation of transgenic mice with representative VHL, EGLN1, and EPAS1 mutants thus represents another avenue by which the HIF-centric model can be tested. So far, polycythemia has been recapitulated in transgenic mice with either VHL loss or EPAS1 gain-of-function mutation. Importantly, a gradient in EPO levels could be discerned between heterozygous and homozygous HIF2α gain-of-function mutation, suggesting this is a sensitive and quantitative readout (Tan et al., 2013). Unfortunately, it’s been difficult to generate a mouse model of pseudohypoxic pheochromocytoma or paraganglioma (Lussey-Lepoutre et al., 2018). One exception is the work of the Bishop group where the inactivation of PHD2 in the Type 1 cells of carotid body resulted in the formation of paraganglioma (Fielding et al., 2018).

Another possible model for testing the HIF-centric hypothesis is the in vitro reconstitution of the entire pVHL-PHD-HIF axis. Purification of PHD2, pVHL-E3 ubiquitin ligase complex, and fluorescein-labeled HIF2α would allow for the real-time monitoring of HIF2α ubiquitylation and degradation. By substituting wild-type components with disease-associated mutations, the level of HIF2α stabilization could be precisely assessed and compared to known clinical phenotypes.

Lastly, the development and clinical evaluation of a specific HIF2α inhibitor, Belzutifan, represents another opportunity to assess the necessity of HIF2α activity for the various clinical manifestations associated with VHL disease (Cho et al., 2016; Chen et al., 2016). Recently, Belzutifan received approval in the US for treatment of RCC, hemangioblastoma, and pancreatic neuroendrocrine tumors (pNET) associated with VHL disease following a successful phase 3 clinical trial (Fallah et al., 2022). A small number of pheochromocytoma tumors in that clinical trial meant that the critical requirement of HIF2α signaling for VHL disease-associated pheochromocytoma could not be assessed, but a single-patient clinical trial of a patient with Pacak-Zhuang syndrome (another name for Class 1a/b HIF2-driven disease) revealed that Belzutifan treatment can result in the shrinkage of paraganglioma tumors and the resolution of polycythemia (Kamihara et al., 2021). Expanded studies evaluating the efficacy of Belzutifan in PPGL tumors associated with VHL disease and HIF2-driven disease will allow for the exploration of the necessity of HIF2α for PPGL in different genetic contexts.

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Author details

1. Michael Ohh

   1. Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada
   2. Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Canada

   Contribution

   Conceptualization, Supervision, Funding acquisition, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   michael.ohh@utoronto.ca

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7600-4751

2. Cassandra C Taber

   Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada

   Contribution

   Data curation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

3. Fraser G Ferens

   1. Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada
   2. Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Canada

   Contribution

   Data curation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6686-1183

4. Daniel Tarade

   Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada

   Contribution

   Conceptualization, Data curation, Writing – original draft, Writing – review and editing

   For correspondence

   daniel.tarade@mail.utoronto.ca

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7029-9640

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