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Section of Medical and Molecular Genetics and Cancer Research UK Renal Molecular Oncology Group, University of Birmingham, Institute of Biomedical Research, Birmingham B15 2TT, UK and West Midlands Regional Genetics Service, Birmingham Women’s Hospital, Birmingham B15 2TG, UK

(Requests for offprints should be addressed to E R Maher at the first address; Email: E.R.Maher{at}bham.ac.uk)

	Abstract

Top Abstract Introduction Clinical phenotype of VHL... Molecular genetics of VHL... Differential diagnosis of... Mechanisms of tumourigenesis VHL protein function References

 
Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome caused by mutations in the VHL tumour suppressor gene. VHL disease is characterised by marked phenotypic variability and the most common tumours are haemangioblastomas of the retina and central nervous system and clear cell renal cell carcinoma. However, endocrine tumours, most commonly phaeochromocytoma and non-secretory pancreatic islet cell cancers, demonstrate marked interfamilial variations in frequency and are significant causes of morbidity and, sometimes, mortality. Genotype–phenotype correlations have revealed that certain missense mutations are associated with a high risk of phaeochromocytoma but total loss of function mutations are associated with a low risk. Furthermore, rare mutations may predispose to a phaeochromocytoma-only phenotype. Germline VHL mutations may be detected in 5–11% of all phaeochromocytoma cases and mutation analysis of VHL and other phaeochromocytoma susceptibility genes (SDHB, SDHD and RET) should be performed in all cases of familial, multiple or early onset phaeochromocytomas, and considered in other cases. The VHL gene product has a key role in regulating the stability of hypoxia-inducible factors (HIF-1 and HIF-2) such that inactivation of VHL leads to up-regulation of HIF-1 and HIF-2 protein expression and activation of hypoxic gene response pathways. Germline SDHB and SDHD mutations also lead to increased expression of HIF target genes, but it appears that phaeochromocytoma susceptibility in VHL disease cannot be attributed to HIF activation alone. Recently, it has been suggested that an HIF-independent failure of developmental apoptosis is a common feature of all inherited phaeochromocytoma susceptibility syndromes.

	Introduction

Top Abstract Introduction Clinical phenotype of VHL... Molecular genetics of VHL... Differential diagnosis of... Mechanisms of tumourigenesis VHL protein function References

 
Although the first descriptions of von Hippel-Lindau (VHL) disease were in the 19th century, phaeochromocytoma was first associated with VHL disease only about 50 years ago (Glushien et al. 1953). Traditionally, an inherited cause of phaeochromocytoma has been estimated to account for ~10% of all cases but the identification of succinate dehydrogenase subunit mutations as a novel cause of familial phaeochromocytoma has prompted increased awareness and interest in the phaeochromocytoma susceptibility (Astuti et al. 2001a,b, Maher & Eng 2002, Neumann et al. 2002). We review the clinical features and molecular genetics of VHL disease with particular emphasis on the link between VHL disease and endocrine tumours.

	Clinical phenotype of VHL disease

Top Abstract Introduction Clinical phenotype of VHL... Molecular genetics of VHL... Differential diagnosis of... Mechanisms of tumourigenesis VHL protein function References

 
VHL disease has a birth incidence of ~1 in 36 000 and ~20% of cases arise as de novo mutations without a family history (Maher et al. 1991, Richards et al. 1995). VHL disease most commonly presents with retinal or cerebellar haemangioblastomas. The third major feature is clear cell renal cell carcinoma, and cystic disease affecting the kidneys, pancreas and epididymis is also frequent. Phaeochromocytoma is a notable feature because of marked interfamilial variation such that although the overall frequency is 10–20%, in many families it is absent while in other kindreds it is the most frequent manifestation of VHL disease (Maher 2004). Pancreatic islet cell tumour is the other major endocrine tumour seen in VHL disease although occasionally hyperparathyroidism and carcinoid have been reported (Binkovitz et al. 1990, Fellows et al. 1990, Hough et al. 1994, Arao et al. 2002, authors’ unpublished observations). Non-endocrine features of VHL disease have been reviewed in detail elsewhere (Maher 2004). The three major features are retinal angiomas (mean age at diagnosis 25 years), central nervous system (CNS) haemangioblastomas (cerebellum (38%, mean age 29 years), spinal cord (58%, mean age 34 years), brainstem (10%) and rarely supratentorial) and clear cell renal cell carcinoma (RCC) (mean age 35–40 years) (see Maher 2004 and references within). In most cases the lifetime risk for developing retinal angioma, CNS haemangioblastoma or clear cell RCC is ~70%, but the precise risk varies according to the nature of the germline mutation (see later). Endolymphatic sac tumours have only been recognised as a complication of VHL disease in the last 10 years but have been reported to occur in up to 11% of patients (Manski et al. 1997).

The mean age at diagnosis of phaeochromocytoma in VHL disease is ~20 years compared with 43.9 years in sporadic cases, reflecting both increased detection through surveillance (see below) and a predisposition to early onset tumours (Maher et al. 1990, Neumann et al. 2002). Phaeochromocytoma in VHL disease is usually intra-adrenal but ~10% are extra-adrenal (Neumann et al. 1993, Walther et al. 1999). Many VHL phaeochromocytomas are asymptomatic at diagnosis and while this is, in part, related to the early diagnosis by routine screening the number of asymptomatic tumours is higher than in other familial disorders such as multiple endocrine neoplasia Type 2 (MEN2). Compared with MEN2, VHL phaeochromocytomas are relatively less likely to express the enzyme phenylethanolamine-N-methyltransferase (PNMT) that converts noradrenaline to adrenaline such that they almost exclusively produce nor-adrenaline. However, in MEN2 there is a relative excess of adrenaline that causes the characteristic clinical manifestations such as tachycardia and episodes of tremulousness (Eisenhofer et al. 2001).

The most frequent pancreatic manifestation of VHL disease is benign serous cysts that occur in up to 90% of VHL patients and rarely cause clinical disease (Neumann et al. 1991, Hough et al. 1994, Hammel 2000). Benign microcystic adenomas also occur in a minority of cases (~12%) (Hammel et al. 2000). More significantly, 5–10% of VHL patients develop pancreatic tumours, most commonly non-secretory islet cell tumours (also known as neuro-endocrine tumours (NET)) which may be multifocal in 50% of affected individuals (Lubensky et al. 1998, Libutti et al. 1998, 2000, Marcos et al. 2002). These tumours are often asymptomatic and are usually detected incidentally during routine abdominal surveillance of VHL patients (Hough et al. 1994, Libutti et al. 1998, Hammel et al. 2000). The mean age at diagnosis of pancreatic NETs in VHL patients is younger than in sporadic cases (35 vs 58 years) (Lubensky et al. 1998). This earlier diagnosis may also contribute to the better prognosis of VHL-associated compared with sporadic NETs. Most VHL NETs are less than 3 cm and are slow growing. Although fewer than 10% metastasise, larger lesions may be more sinister and Marcos et al. (2002) found that ~20% of lesions >3.0 cm in diameter had metastasised to the liver.

	Molecular genetics of VHL disease

Top Abstract Introduction Clinical phenotype of VHL... Molecular genetics of VHL... Differential diagnosis of... Mechanisms of tumourigenesis VHL protein function References

 
The VHL tumour suppressor gene comprises 3 exons and encodes two proteins, a full length 213 amino acid protein, which migrates with an apparent molecular weight of ~28–30 kDa and a shorter 160 amino acid protein translated from an internal translation initiation site at codon 54. The 4.7 kb mRNA is widely expressed in both fetal and adult tissues, thus differential tissue expression does not account for the tissue-specific manifestations of VHL disease (Latif et al. 1993, Richards et al. 1996). Germline VHL mutations have been characterised in >500 patients and have provided a wealth of data for genotype–phenotype correlations (see later). VHL mutations may cause (a) VHL disease, (b) isolated familial phaeochromocytoma (Type 2C VHL disease) and (c) autosomal recessively inherited polycythaemia due to homozygous missense mutations (e.g. c.C811T, R200w in Chuvash polycythaemia) (Latif et al. 1993, Crossey et al. 1994, 1995, Chen et al. 1995, Neumann et al. 1995, Zbar et al. 1996, Woodward et al. 1997, Ang et al. 2002, Pastore et al. 2003). Among patients with VHL disease, ~40% of mutations are genomic deletions and the rest are predominantly truncating or missense mutations (which do not occur within the first 53 amino acids). Most intragenic mutations are restricted to a small number of families but notable exceptions are recurrent missense mutations at a CpG mutation hotspot at codon 167 (e.g. p.R167W and p.R167Q) and the p.Y98H missense founder mutation that originated in South-West Germany (the ‘Black Forest’ mutation) (Brauch et al. 1995, Richards et al. 1995).

The phenotypic variability that is characteristic of VHL disease may reflect mosaicism or modifier effects, but allelic heterogeneity is the major cause (Crossey et al. 1994, Webster et al. 1998, Sgambati et al. 2000). Thus, there are complex genotype–phenotype correlations in VHL disease particularly with regard to the presence or absence of phaeochromocytoma. VHL disease has been divided into Type 1 kindreds (in which affected individuals may have retinal or CNS haemangioblastomas and RCC but not phaeochromocytoma) and Type 2 kindreds (at least one affected individual has phaeochromocytoma). Type 2 kindreds are further subdivided into Type 2A (in which retinal and CNS haemangioblastomas but rarely RCC occur) and Type 2B (haemangioblastomas, RCC and phaeochromocytoma occur) (Crossey et al. 1994, Brauch et al. 1995, Maher et al. 1996, Zbar et al. 1996). Subsequently, a subset of families with isolated familial phaeochromocytoma were shown to have germline VHL gene missense mutations (Type 2C VHL disease) (Crossey et al. 1995, Neumann et al. 1995, Woodward et al. 1997). Whilst in some cases this reflected variable expression (e.g. p.R167w mutations that are usually associated with a Type 2B phenotype were found), in other families the mutation had not been described in other subtypes and appeared to be associated with a phaeochromocytoma only phenotype. Most patients with Type 2 VHL disease have missense mutations whereas in Type 1 families large deletions and truncating mutations predominate (Crossey et al. 1994, Maher et al. 1996, Zbar et al. 1996). Thus, it appeared that complete loss of function mutations were associated with a low risk of phaeochromocytoma, implying that Type 2 missense mutations may retain some functional activity. Consistent with this hypothesis, it was subsequently demonstrated that many missense mutations causing a Type 1 phenotype involved core hydrophobic residues and were predicted to disrupt protein structure, whereas Type 2 phenotype missense mutations involved substitutions at a surface amino acid that does not cause a total loss of function (Stebbins et al. 1999). Although no specific genotype–phenotype correlations have been defined for pancreatic NETs occurring in VHL disease, it has been observed that they may be more frequently associated with phaeochromocytoma (Binkovitz et al. 1990, Marcos et al. 2002). Thus Marcos et al. (2002) reported that up to 40% of VHL patients with a pancreatic NET had a surgically confirmed adrenal phaeochromocytoma. Such an association may reflect their shared embryonic neural crest origins and common mechanisms of tumourigenesis.

	Differential diagnosis of familial phaeochromocytoma

Top Abstract Introduction Clinical phenotype of VHL... Molecular genetics of VHL... Differential diagnosis of... Mechanisms of tumourigenesis VHL protein function References

 
Phaeochromocytoma susceptibility is associated with VHL disease, multiple endocrine neoplasia Types 2A and 2B, neurofibromatosis Type 1 (NF1) and also succinate dehydrogenase (SDH) subunit mutations. Whilst the clinical features of MEN2 and NF1 are well known, SDH subunit mutations were recognised to cause susceptibility to phaeochromocytoma and head and neck paraganglioma relatively recently (Baysal et al. 2000, Grimm et al. 2000, Astuti et al. 2001a,b, Niemann & Muller 2000). Germline mutations in three (SDHB, SDHC and SDHD) of the four SDH subunits have been associated with inherited phaeochromocytoma, but germline mutations in SDHC are rare (Niemann & Muller 2000). In patients presenting with familial, childhood or multicentric phaeochromocytoma, 30–40% will have a germline VHL mutation and a similar proportion of germline SDHD or SDHB mutation (Woodward et al. 1997, Astuti et al. 2001b, authors’ unpublished observations). In an unselected series of phaeochromocytoma cases, ~25% had a germline VHL (11%), SDHB (5%), SDHD (4%) or RET (MEN2) (5%) mutation (Neumann et al. 2002). However, in other series the frequency has been lower (15–20%) although this is still significantly higher than the ‘classic’ 10% (Gimenez-Roqueplo et al. 2003, authors’ unpublished observations). Compared with patients with germline VHL or RET mutations, there is an increased frequency of extra-adrenal phaeochromocytomas (and head and neck paragangliomas) in individuals with SDHB and SDHD mutations, and an increased rate of malignancy in those with SDHB mutations. Although VHL disease, MEN2 and SDHB mutations show autosomal dominant transmission patterns (albeit with variable expression and age-dependent penetrance), SDHD mutations only cause disease after paternal transmission and an individual who inherits the mutation from their mother will be clinically unaffected (Baysal et al. 2000, Astuti et al. 2001a).

	Mechanisms of tumourigenesis

Top Abstract Introduction Clinical phenotype of VHL... Molecular genetics of VHL... Differential diagnosis of... Mechanisms of tumourigenesis VHL protein function References

 
The VHL tumour suppressor gene (TSG) has features of a classical retinoblastoma-like TSG in that all tumour types from VHL patients may demonstrate inactivation of the wild-type VHL allele by allele loss, mutation or methylation (Prowse et al. 1997). Furthermore, sporadic clear cell RCC and sporadic haemangioblastomas may demonstrate somatic inactivation and loss, resulting in biallelic VHL inactivation (Foster et al. 1994, Gnarra et al. 1994, Kanno et al. 1994). However, somatic VHL mutations are rare in phaeochromocytoma and, interestingly, somatic inactivation of RET, SDHB and SDHD is also infrequent in sporadic phaeochromocytomas (Eng et al. 1995, Astuti et al. 2001b, 2003).

	VHL protein function

Top Abstract Introduction Clinical phenotype of VHL... Molecular genetics of VHL... Differential diagnosis of... Mechanisms of tumourigenesis VHL protein function References

 
The identification of the VHL gene did not provide any immediate clues to the function of the VHL protein (pVHL) as the protein sequence did not resemble any known protein (Latif et al. 1993). However, pVHL was shown to form a tetrameric (VCBC) complex with elongins B and C and Cul2 (a member of the cullin family) (Pause et al. 1997, Lonergan et al. 1998). In addition, structural homologies were noted between the VCBC complex and the yeast SCF complex which regulates proteosomal degradation of protein targets specified by the F-box component. Thus, targeted proteins are tagged for degradation by the addition of a ubiquitin tail by a ubiquitin ligase (Lonergan et al. 1998). Moreover, the Rbx-1 protein (a key component of SCF complexes) was then shown to associate with the VCBC complex (Kamura et al. 1999).

VHL-related tumours are highly vascular and demonstrate over-production of hypoxia-inducible mRNAs such as vascular endothelial growth factor (VEGF) (Wizigmann-Voos et al. 1995). Many hypoxia-inducible mRNAs are under the control of heterodimeric transcription factors (HIF-1 and HIF-2), which consist of a degradable alpha subunit and a stable constitutively expressed beta subunit (Schofield & Ratcliffe 2004). Under normoxic conditions, HIF-1 and HIF-2 are rapidly polyubiquitylated and destroyed by the proteosome, but under hypoxic conditions the alpha subunits are stabilised and HIF-1 and HIF-2 activate transcription of a wide repertoire of hypoxia-inducible mRNAs (Schofield & Ratcliffe 2004 and references within).

The crucial link between pVHL and the regulation of hypoxia-inducible mRNAs was provided by Maxwell and colleagues who showed that pVHL interacts with the regulatory alpha subunit of HIF and targets it for oxygen-dependent polyubiquitylation and proteosomal degradation (Maxwell et al. 1999, Cockman et al. 2000). pVHL mutants failed to degrade the alpha subunits leading to stabilisation of HIF-1 and HIF-2 and inappropriate expression of hypoxia-inducible mRNAs (see Fig. 1). The oxygen-dependent interaction of pVHL with HIF- is provided by the hydroxylation status of key HIF- proline residues (Pro-402 and Pro-564) (Ivan et al. 2001, Jaakkola et al. 2001, Masson et al. 2001, Yu et al. 2001). Thus, in the presence of oxygen, HIF- subunits are hydroxylated at the conserved prolyl residues by members of the egg laying defective nine (EGLN) family (also known as the PHD family) (Bruick & McKnight 2001, Epstein et al. 2001). Molecular oxygen and 2-oxoglutarate are essential cosubstrates and iron is an essential cofactor (Epstein et al. 2001, Schofield & Ratcliffe 2004) and, in the absence of these, hydroxylation does not occur and pVHL is unable to bind the alpha subunits. In humans, three EGLN homologues have been implicated in HIF- modification (PHD1/EglN2/HIFPH1, PHD2/EglN1/HIFPH2 and PHD3/EglN3/HIFPH3) (Bruick & McKnight 2001, Epstein et al. 2001).

View larger version (23K): [in this window] [in a new window]   Figure 1 Relationship between VHL protein (pVHL) and regulation of hypoxia-inducible factor- subunits. (A) Under normoxic conditions, pVHL binds to HIF- subunits leading to ubiquitylation and proteosomal degradation. The ability of pVHL to bind an HIF- subunit is dependent on hydroxylation of two proline residues (POH). (B) In a tumour with pVHL inactivation, the lack of wild-type pVHL allows HIF- and HIF-ß subunits to interact and the heterodimeric transcription factors activate expression of a wide repertoire of hypoxia-inducible genes. (C) In hypoxia, the two critical proline residues in the subunit are not hydroxylated (P) and pVHL is unable to bind HIF-, leading to activation of the hypoxia-inducible gene response.

The precise role of HIF dysregulation in the pathogenesis of VHL-related phaeochromocytomas is unclear. Thus both Type 2A and Type 2B VHL mutations (associated with a high risk of phaeochromocytoma) are unable to regulate HIF (Clifford et al. 2001) and comparison of gene expression patterns in VHL and MEN2 phaeochromocytomas revealed that many of the genes over-expressed in VHL compared with MEN2 tumours were linked to the hypoxia-driven angiogenic pathways (e.g. VEGF, placental growth factor, angiopoietin 2, tie-1, VEGF receptor 2 and neuropilin-1) (Eisenhofer et al. 2004). Phaeochromocytomas from SDHB and SDHD gene carriers demonstrate evidence of HIF activation and over-expression of hypoxia-inducible genes (Gimenez-Roqueplo et al. 2001, Pollard et al. 2005) and SDH inactivation has been shown in vitro to inhibit HIF- prolyl hydroxylases leading to stabilisation and activation of HIF-1, further implicating HIF dysregulation in phaeochromocytoma tumourigenesis (Selak et al. 2005). Furthermore, comparison of gene expression profiles in VHL-, SDHB- and SDHD-associated phaeochromocytomas demonstrated a shared transcription profile of reduced oxidoreductase and increased angiogenesis/hypoxia target genes (Dahia et al. 2005). However, the role of HIF-1 and HIF-2 in phaeochromocytoma tumourigenesis may be complex because Type 1 VHL mutations (with a low risk of phaeochromocytoma) are also unable to regulate HIF, and Type 2C (phaeochromocytoma only) pVHL mutants retain the ability to regulate HIF- subunit degradation, suggesting that HIF dysregulation is not essential for the development of phaeochromocytomas in VHL disease (Clifford et al. 2001, Hoffman et al. 2001). Hence, it was suggested that the complex genotype–phenotype relationships observed in VHL disease were consistent with multiple and tissue-specific functions.

Recently, Lee et al. (2005) have suggested a novel HIF-independent pVHL function that links phaeochromocytoma in VHL disease to that in other familial phaeochromocytoma predisposition syndromes. Thus, they hypothesised that inherited phaeochromocytomas originate from sympathetic neuronal precursor cells that usually undergo c-Jun dependent apoptosis during embryogenesis when growth factors such as nerve growth factor (NGF) become limiting (Estus et al. 1994, Schlingensiepen et al. 1994, Ham et al. 1995, Xia et al. 1995) (see Fig. 2). JunB is an antagonist of c-Jun such that increased levels of JunB attenuate c-Jun induced apoptosis in phaeochromocytoma cells with NGF withdrawal. Pathogenic NF1 and RET mutations are known to enhance signalling by NGF receptors and hence promote neuronal survival (Vogel et al. 1995, Dechant 2002). Lee et al. (2005) found that all pVHL mutants tested (including 2C mutants that retain the ability to degrade HIF) failed to down-regulate JunB following NGF withdrawal, thus promoting cell survival (the pVHL effect on JunB is mediated, in part, through an HIF-independent, atypical protein kinase C pathway). Furthermore, a similar effect was also demonstrated with activating mutations of RET. EglN3 (PHD3) (a member of the proline hydroxylase EGLN family) had previously been shown to be induced in sympathetic neurons following NGF withdrawl and to provoke apoptosis when over-expressed in phaeochromocytoma cells (Lipscomb et al. 1999, 2001, Straub et al. 2003) and Lee et al. (2005) reported (a) that EglN3, but not EglN1, acts downstream of c-Jun and is both necessary and sufficient to induce neuronal apoptosis following NGF withdrawal and (b) that EglN3 is sensitive to changes in SDH activity such that after SDH inactivation, succinate accumulation inhibits the activity of EglN3 thus preventing apoptosis of the neuronal precursor cells. Although SDH is a mitochondrial enzyme, the succinate that accumulates is transported to the cytosol by the dicarboxylate carrier located on the inner mitochondrial membrane. Thus, these findings provide a common link between phaeochromocytoma development in inherited phaeochromocytoma susceptibility syndromes as (a) NF1 inhibits downstream signalling by the NGF receptor, TrkA, and loss of NF1 promotes NGF independent survival of embryonic peripheral neurons (Vogel et al. 1995) and (b) activation of RET, like loss of pVHL, has been shown to lead to the induction of JunB and thus attenuates apoptosis after NGF withdrawal. In addition, the concept that germline NF1, RET, SDH subunit and VHL mutations promote phaeochromocytoma development by allowing sympathetic neuronal progenitors to escape from developmental apoptosis is consistent with the observation that somatic inactivation of these genes is infrequent in sporadic phaeochromocytoma (whereas somatic VHL inactivation occurs in most sporadic clear cell RCC) (Maher & Eng 2002). It should be noted that whereas all pVHL mutants fail to down-regulate JunB (including Type 1 mutants which are not associated with phaeochromocytoma), pVHL has multiple effects on EglN3, and Type 1 and Type 2 pVHL mutants differ with respect to their effect on EglN3/PHD3 expression (increased in Type 1 mutants). Thus, Type 1 mutations increase EglN3 expression whereas Type 2 mutations result in reduced EglN3 expression.

View larger version (18K): [in this window] [in a new window]   Figure 2 Model of phaeochromocytoma in von Hippel-Lindau disease (Lee et al. 2005). (Top panel) In normal development as nerve growth factor (NGF) levels become limiting, sympathetic neuronal precursor cells proceed to apoptosis via a cJun/EglN3 pathway. Whilst the pro-apoptotic effect of cJun is antagonised by JunB, pVHL inhibits JunB expression so that apoptosis is favoured. (Lower panel) In the presence of a Type 2 pVHL mutant, the failure of pVHL-induced repression of JunB anatagonises cJun and EglN3 such that some sympathetic neuronal precursor cells fail to undergo apoptosis and may develop into a phaeochromocytoma.

	Acknowledgements

 
The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

	References

Top Abstract Introduction Clinical phenotype of VHL... Molecular genetics of VHL... Differential diagnosis of... Mechanisms of tumourigenesis VHL protein function References

 
Acker T, Diez-Juan A, Aragones J, Tjwa M, Brusselmans K, Moons L, Fukumura D, Moreno-Murciano MP, Herbert JM, Burger A, Riedel J, Elvert G, Flamme I, Maxwell PH, Collen D, Dewerchin M, Jain RK, Plate KH & Carmeliet P 2005 Genetic evidence for a tumor suppressor role of HIF-2alpha. Cancer Cell 8 131–141.[CrossRef][ISI][Medline]

Ang SO, Chen H, Hirota K, Gordeuk VR, Jelinek J, Guan Y, Liu E, Sergueeva AI, Miasnikova GY, Mole D et al. 2002 Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nature Genetics 32 614–621.[CrossRef][ISI][Medline]

Arao T, Okada Y, Tanikawa T, Inatomi H, Shuin T, Fujihira T, Yamashita H & Tanaka Y 2002 A case of von Hippel-Lindau disease with bilateral pheochromocytoma, renal cell carcinoma, pelvic tumor, spinal hemangioblastoma and primary hyperparathyroidism. Endocrinology Journal 49 181–188.

Astuti D, Douglas F, Lennard TWJ, Aligianis I, Woodward ER, Evans DGR, Eng C, Latif F & Maher ER 2001a Germline SDHD mutation in familial phaeochromocytoma. Lancet 357 1181–1182.[CrossRef][ISI][Medline]

Astuti D, Latif F, Dallol A, Dahia PLM, Douglas F, George E, Skoldberg F, Husebye ES, Eng C & Maher ER 2001b Mutations in the mitochondrial complex II subunit SDHB cause susceptibility to familial paraganglioma and pheochromocytoma. American Journal of Human Genetics 69 49–54.[CrossRef][ISI][Medline]

Astuti D, Hart-Holden N, Latif F, Lalloo F, Black GC, Lim C, Moran A, Grossman AB, Hodgson S, Freemont A et al. 2003 Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility. Clinical Endocrinology 59 728–733.[CrossRef][Medline]

Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Tashner PE, Rubinstein WS, Myers EN et al. 2000 Mutations in SDHD, a mitochondrial complex II gene in hereditary paraganglioma. Science 287 848–851.[Abstract/Free Full Text]

Binkovitz LA, Johnson CD & Stephens DH 1990 Islet cell tumors in von Hippel-Lindau disease: increased prevalence and relationship to the multiple endocrine neoplasias. American Journal of Roentgenology 162 1091–1094.

Brauch H, Kishida T, Glavac D, Chen F, Pausch F, Hofler H, Latif F, Lerman MI, Zbar B & Neumann HPH 1995 Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect. Human Genetics 95 551–556.[ISI][Medline]

Bruick RK & McKnight SL 2001 A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294 1337–1340.[Abstract/Free Full Text]

Chen F, Kishida T, Yao M, Hustad T, Glavac D, Dean M, Gnarra JR, Orcutt ML, Duh FM, Glenn G et al. 1995 Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Human Mutation 5 66–75.[CrossRef][ISI][Medline]

Clifford SC, Cockman ME, Smallwood AC, Mole DR, Woodward ER, Maxwell PH, Ratcliffe PJ & Maher ER 2001 Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumorigenesis in von Hippel-Lindau disease. Human Molecular Genetics 10 1029–1038.[Abstract/Free Full Text]

Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ & Maxwell PH 2000 Hypoxia-inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. Journal of Biological Chemistry 275 25733–25741.[Abstract/Free Full Text]

Crossey PA, Richards FM, Foster K, Green JS, Prowse A, Latif F, Lerman MI, Zbar B, Affara NA, Ferguson-Smith MA et al. 1994 Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Human Molecular Genetics 3 1303–1308.[Abstract/Free Full Text]

Crossey PA, Eng C, Ginalska-Malinowska M, Lennard TWJ, Sampson JR, Ponder BAJ & Maher ER 1995 Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma. Journal of Medical Genetics 32 885–886.[Abstract]

Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, Tischler AS et al. 2005 A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. Public Library of Science Genetics 1 72–80.[Medline]

Dechant G 2002 Chat in the trophic web: NGF activates Ret by inter RTK signalling. Neuron 33 156–158.[CrossRef][ISI][Medline]

Devarajan P, De Leon M, Talasazan F, Schoenfeld AR, Davidowitz EJ & Burk RD 2001 The von Hippel-Lindau gene product inhibits renal cell apoptosis via Bcl-2-dependent pathways. Journal of Biological Chemistry 276 40599–40605.[Abstract/Free Full Text]

Eisenhofer G, Walther MM, Huynh TT, Li ST, Bornstein SR, Vortmeyer A, Mannelli M, Goldstein DS, Linehan WM, Lenders JW et al. 2001 Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. Journal of Clinical Endocrinology and Metabolism 86 1999–2008.[Abstract/Free Full Text]

Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM, Munson PJ, Mannelli M, Goldstein DS & Elkahloun AG 2004 Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. Endocrine-Related Cancer 11 897–911.[Abstract/Free Full Text]

Eng C, Crossey PA, Mulligan LM, Healey CS, Houghton C, Prowse A, Chew SL, Dahia PL, O’Riordan JL, Toledo SP et al. 1995 Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas. Journal of Medical Genetics 32 934–937.[Abstract]

Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A et al. 2001 C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107 43–54.[CrossRef][ISI][Medline]

Estus S, Zaks WJ, Freeman RS, Gruda M, Bravo R & Johnson EM Jr 1994 Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis. Journal of Cell Biology 127 1717–1727.[Abstract/Free Full Text]

Fellows IW, Leach IH, Smith PG, Toghill PJ & Doran J 1990 Carcinoid tumour of the common bile duct – a novel complication of von Hippel-Lindau syndrome. Gut 31 728–729.[Abstract/Free Full Text]

Foster K, Prowse A, van den Berg A, Fleming S, Hulsbeek MM, Crossey PA, Richards FM, Cairns P, Affara NA, Ferguson-Smith MA et al. 1994 Somatic mutations of the von Hippel–Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Human Molecular Genetics 3 2169–2173.[Abstract/Free Full Text]

Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol P, Rotig A & Jeunemaitre X 2001 The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. American Journal of Human Genetics 69 1186–1197.[CrossRef][ISI][Medline]

Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin PF, Jeunemaitre X et al. 2003 Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Research 63 5615–5621.[Abstract/Free Full Text]

Glushien AS, Mansuy MM & Littman DS 1953 Pheochromocytoma. Its relationship to the neurocutaneous syndromes. American Journal of Medicine 14 318–327.[CrossRef][ISI][Medline]

Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, Latif F, Liu S, Chen F, Duh FM et al. 1994 Mutations of the VHL tumour suppressor gene in renal carcinoma. Nature Genetics 7 85–90.[CrossRef][ISI][Medline]

Grimm O, Armanios M, Dziema H, Neumann HPH & Eng C 2000 Somatic and occult germline mutations in SDHD, a mitochondrial complex II gene, in non-familial pheochromoctyoma. Cancer Research 60 6822–6825.[Abstract/Free Full Text]

Ham J, Babij C, Whitfiels J, Pfarr CM, Lallemand D, Yaniv M & Rubin LL 1995 A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death. Neuron 14 927–939.[CrossRef][ISI][Medline]

Hammel PR, Vilgrain V, Terris B, Penfornis A, Sauvanet A, Correas JM, Chauveau D, Balian A, Beigelman C, O’Toole D et al. 2000 Pancreatic involvement in von Hippel-Lindau disease. The Groupe Francophone d’Etude de la Maladie de von Hippel-Lindau. Gastroenterology 119 1087–1095.[CrossRef][ISI][Medline]

Hergovich A, Lisztwan J, Barry R, Ballschmieter P & KrekW 2003 Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. Nature Cell Biology 5 64–70.[CrossRef][ISI][Medline]

Hoffman MA, Ohh M, Yang H, Klco JM, Ivan M & Kaelin WG Jr 2001 von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Human Molecular Genetics 10 1019–1027.[Abstract/Free Full Text]

Hough MT, Stephens DH, Johnson CD & Binkovitz LA 1994 Pancreatic lesions in von Hippel-Lindau disease: prevalence, clinical significance, and CT findings. American Journal of Roentgenology 162 1091–1094.[Abstract/Free Full Text]

Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS & Kaelin WG Jr 2001 HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O₂ sensing. Science 292 464–468.[Abstract/Free Full Text]

Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ et al. 2001 Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O₂-regulated prolyl hydroxylation. Science 292 468–472.[Abstract/Free Full Text]

Kamura T, Koepp DM, Conrad MN, Skowyra D, Moreland RJ, Iliopoulos O, Lane WS, Kaelin WG Jr, Elledge SJ, Conaway RC et al. 1999 Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science 284 657–661.[Abstract/Free Full Text]

Kanno H, Kondo K, Ito S, Yamamoto I, Fujii S, Torigoe S, Sakai N, Hosaka M, Shuin T & Yao M 1994 Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas. Cancer Research 54 4845–4847.[Abstract/Free Full Text]

Kondo K, Klco J, Nakamura E, Lechpammer M & Kaelin WG Jr 2002 Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 1 237–246.[CrossRef][ISI][Medline]

Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L et al. 1993 Identification of the von Hippel-Lindau disease tumour suppressor gene. Science 260 1317–1320.[Abstract/Free Full Text]

Lee S, Nakamura E, Yang H, Wei W, Linggi MS, Sajan MP, Farese RV, Freeman RS, Carter BD, Kaelin WG Jr et al. 2005 Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial phaeochromocytoma genes: developmental culling and cancer. Cancer Cell 8 1–13.[CrossRef][ISI][Medline]

Libutti SK, Choyke PL, Bartlett DL, Vargas H, Walther M, Lubensky I, Glenn G, LinehanWM& Alexander HR 1998 Pancreatic neuroendocrine tumors associated with von Hippel-Lindau disease: diagnostic and management recommendations. Surgery 124 1153–1159.[CrossRef][ISI][Medline]

Libutti SK, Choyke PL, Alexander HR, Glenn G, Bartlett DL, Zbar B, Lubensky I, McKee SA, Maher ER & Linehan WM 2000 Clinical and genetic analysis of patients with pancreatic neuroendocrine tumors associated with von Hippel-Lindau disease. Surgery 128 1022–1027.[CrossRef][ISI][Medline]

Lipscomb E, Sarmiere P, Crowder R & Freeman R 1999 Expression of the SM-20 gene promotes death in nerve growth factor-dependent sympathetic neurons. Journal of Neurochemistry 73 429–432.[CrossRef][ISI][Medline]

Lipscomb E, Sarmiere P & Freeman R 2001 SM-20 is a novel mitochondrial protein that causes caspase-dependent cell death in nerve growth factor-dependent neurons. Journal of Biological Chemistry 276 11775–11782.[Abstract/Free Full Text]

Lonergan KM, Iliopoulos O, Ohh M, Kamura T, Conaway RC, Conaway JW & Kaelin WG Jr 1998 Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Molecular and Cellular Biology 18 732–741.[Abstract/Free Full Text]

Lubensky IA, Pack S, Ault D, Vortmeyer AO, Libutti AK, Choyke PL, Walther McCM, Linehan WM & Xhaung Z 1998 Mulitple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients. American Journal of Pathology 153 223–231.[Abstract/Free Full Text]

Maher ER 2004 Von Hippel-Lindau disease. Current Molecular Medicine 4 833–842.[CrossRef][ISI][Medline]

Maher ER & Eng C 2002 The pressure rises: update in the genetics of phaeochromocytoma. Human Molecular Genetics 11 2347–2354.[Abstract/Free Full Text]

Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT & Ferguson-Smith MA 1990 Clinical features and natural history of von Hippel-Lindau disease. Quarterly Journal of Medicine 77 1151–1163.[Abstract/Free Full Text]

Maher ER, Iselius L, Yates JR, Littler M, Benjamin C, Harris R, Sampson J, Williams A, Ferguson-Smith MA & Morton N 1991 Von Hippel-Lindau disease: a genetic study. Journal of Medical Genetics 28 443–447.[Abstract]

Maher ER, Webster AR, Richards FM, Green JS, Crossey PA, Payne SJ & Moore AT 1996 Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations. Journal of Medical Genetics 33 328–332.[Abstract]

Manski TJ, Heffner DK, Glenn GM, Patronas NJ, Pikus AT, Katz D, Lebovics R, Sledjeski K, Choyke PL, Zbar B et al. 1997 Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease. Journal of the American Medical Association 277 1461–1466.[Abstract]

Maranchie JK, Vasselli JR, Riss J, Bonifacino JS, Linehan WM & Klausner RD 2002 The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 1 257–255.[CrossRef][ISI][Medline]

Marcos HB, Libutti SK, Alexander HR, Lubensky IA, Bartlett DL, Walther McCM, Linehan WM, Glenn GM& Choyke PL 2002 Neuroendocrine tumours of the pancreas in von Hippel-Lindau disease: spectrum of appearances at CT and MR imaging with histopathologic comparison. Radiology 225 751–758.[Abstract/Free Full Text]

Masson N, Willam C, Maxwell PH, Pugh CW & Ratcliffe PJ 2001 Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO Journal 20 5197–5206.[CrossRef][ISI][Medline]

Maxwell PH, Wiesener MS, Chang GT-W, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER & Ratcliff PJ 1999 The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399 271–275.[CrossRef][Medline]

Neumann HP, Dinkel E, Brambs H, Wimmer B, Friedburg H, Volk B, Sigmund G, Riegler P, Haag K, Schollmeyer P et al. 1991 Pancreatic lesions in the von Hippel-Lindau syndrome. Gastroenterology 101 465–471.[ISI][Medline]

Neumann HP, Eng C, Mulligan LM, Glavac D, Zauner I, Ponder BA, Crossey PA, Maher ER & Brauch H 1995 Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II. Journal of the American Medical Association 274 1149–1151.[Abstract]

Neumann HPH, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoeffer C, Zerres K et al. 2002 Germline mutations in nonsyndromic phaeochromocytoma. New England Journal of Medicine 346 1459–1466.[Abstract/Free Full Text]

Niemann S & Muller U 2000 Mutations in SDHC cause autosomal dominant paraganglioma. Nature Genetics 26 141–150.[CrossRef][ISI][Medline]

Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer Rachamimov AO, Louis DN, Gavin BJ, Kley N, Kaelin WG Jr & Iliopoulos O 1998 The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Molecular Cell 1 959–968.[CrossRef][ISI][Medline]

Pastore Y, Jedlickova K, Guan Y, Liu E, Fahner J, Hasle H, Prchal JF & Prchal JT 2003 Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia. American Journal of Human Genetics 73 412–419.[CrossRef][ISI][Medline]

Pause A, Lee S, Worrell RA, Chen DYT, Burgess WH, Linehan WM & Klausner RD 1997 The von Hippel- Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. PNAS 94 2156–2161.[Abstract/Free Full Text]

Pioli PA & Rigby WF 2001 The von Hippel-Lindau protein interacts with heteronuclear ribonucleoprotein a2 and regulates its expression. Journal of Biological Chemistry 276 40346–44052.[Abstract/Free Full Text]

Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ et al. 2005 Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Human Molecular Genetics 14 2231–2239.[Abstract/Free Full Text]

Prowse AH, Webster AR, Richards FM, Richard S, Olschwang S, Resche F, Affara NA & Maher ER 1997 Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors. American Journal of Human Genetics 60 765–771.[ISI][Medline]

Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, Li JL, Pugh CW, Maxwell PH, Harris AL & Ratcliffe PJ 2005 Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Molecular and Cellular Biology 25 5675–5686.[Abstract/Free Full Text]

Richards FM, Payne SJ, Zbar B, Affara NA, Ferguson-Smith MA & Maher ER 1995 Molecular analysis of de novo germline mutations in the von Hippel-Lindau disease gene. Human Molecular Genetics 4 2139–2143.[Abstract/Free Full Text]

Richards FM, Schofield PN, Fleming S & Maher ER 1996 Expression of the von Hippel-Lindau disease tumour suppressor gene during human embryogenesis. Human Molecular Genetics 5 639–644.[Abstract/Free Full Text]

Schlingensiepen KH, Wollink F, Kunst M, Schlingensiepen R, Herdegen T & Brysch W 1994 The role of Jun transcription factor expression and phosphorylation in neuronal differentiation, neuronal cell death, and plastic adaptations in vivo. Cellular and Molecular Neurobiology 14 487–505.[CrossRef][ISI][Medline]

Schofield CJ & Ratcliffe PJ 2004 Oxygen sensing by HIF hydroxylases. Nature Reviews Molecular Cell Biology 5 343–354.[CrossRef][ISI][Medline]

Selak MA, Armour SA, Mackenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB & Gottlieb E 2005 Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7 77–85.[CrossRef][ISI][Medline]

Sgambati MT, Stolle C, Choyke PL, Walther MM, Zbar B, Linehan WM & Glenn GM 2000 Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents. Americal Journal of Human Genetics 66 84–91.

Stebbins CE, Kaelin WG Jr & Pavletich NP 1999 Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science 284 455–461.[Abstract/Free Full Text]

Straub JA, Lipscomb EA, Yoshuida ES & Freeman RS 2003 Induction of SM-20 in PC12 cells leads to increased cytochrome c levels, accumulation of cytochrome c in the cytosol, and caspase-dependent cell death. Journal of Neurochemistry 85 318–328.[ISI][Medline]

Vogel KS, Brannan CI, Jenkins NA, Copeland NG & Parad LF 1995 Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons. Cell 82 733–742.[CrossRef][ISI][Medline]

Walther MM, Retier R, Keiser HR, Choyke PL, Venzon D, Hurley K, Gnarra JR, Reynolds JC, Glenn GM & Zbar B 1999 Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. Journal of Urology 162 659–664.[CrossRef][ISI][Medline]

Webster AR, Richards FM, MacRonald FE, Moore AT & Maher ER 1998 An analysis of phenotypic variation in the familial cancer syndrome von Hippel-Lindau disease: evidence for modifier effects. American Journal of Human Genetics 63 1025–1035.[CrossRef][ISI][Medline]

Wizigmann-Voos S, Breier G, Risau W & Plate KH 1995 Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Research 55 1358–1364.[Abstract/Free Full Text]

Woodward ER, Eng C, McMahon R, Voutilainen R, Affara NA, Ponder BAJ & Maher ER 1997 Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. Human Molecular Genetics 6 1051–1056.[Abstract/Free Full Text]

Xia Z, Dickens M, Raingeaud J, Davis RJ & Greenberg ME 1995 Opposing effects of ERK and JNK-p38 MAP kinases in apoptosis. Science 270 1326–1331.[Abstract/Free Full Text]

Yu F, White SB, Zhao Q & Lee FS 2001 HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. PNAS 98 9630–9635.[Abstract/Free Full Text]

Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey PA, Webster AR, Affara NA, Ferguson- Smith MA et al. 1996 Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Human Mutation 8 348–357.[CrossRef][ISI][Medline]

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