Open access

Missense Mutation in Cancer in Correlation to Its Phenotype – VHL as a Model

Written By

Suad AlFadhli

Submitted: 25 May 2011 Published: 12 October 2012

DOI: 10.5772/36727

From the Edited Volume

Mutations in Human Genetic Disease

Edited by David N. Cooper and Jian-Min Chen

Chapter metrics overview

2,168 Chapter Downloads

View Full Metrics

1. Introduction

Cancer is a complex genetic disease caused by abnormal alteration (mutations) in DNA sequences that leads to dyregulation of normal cellular processes thereby driving tumor growth. The study of such causal mutations is a central focus of cancer biology for two reasons; first is to reveal the molecular mechanisms of tumorigenesis, second is to provide insight in the development of novel therapeutic and diagnostic approaches. Although hundreds of genes are known to be mutated in cancers our understanding of mutational events in cancer cells remains incomplete (Futreal PA et al, 2004). This however has widely opened the field of cancer genomics studies which aims to provide new insights into the molecular mechanisms that lead to tumorigenesis.

As we are in the era of evidence-based molecular diagnosis, predictive testing, genetic counseling, gene-informed cancer risk assessment, and preventative and personalized medicine, therefore, studying the Mendelian genetics of the familial forms of cancer is one approach that can set up the basis for gene-informed risk assessment and management for the patient and family. Herein we selected a Mendelian genetics form of familial cancer such as hereditary tumor syndromic endocrine neoplasias caused by highly penetrant germline mutations leading to pheochromocytoma-paraganglioma syndromes. An example of such syndromes are autosomal dominant disorders; von Hippel-Lindau (VHL); Multiple endocrine neoplasia syndrome type 1 (MEN-1), loss-of-function germline mutations in the tumor suppressor gene MEN1 increase the risk of developing pituitary, parathyroid and pancreatic islet tumors, and less commonly thymic carcinoids, lipomas and benign adrenocortical tumors. In the case of multiple endocrine neoplasia type 2 (MEN 2), gain-of-function germline mutations clustered in specific codons of the RET proto-oncogene increase the risk of developing medullary thyroid carcinoma (MTC), phaeochromocytoma and parathyroid tumors. PTEN mutations in Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Identification and characterization of germline mutations in the predisposition genes of the great majority of these syndromes has empowered the clinical practice by the retrieved genetic information which guides medical management.

This review focuses specifically on the analysis of missense mutations in oncogenes and the tumor suppressor genes, though these genes can also be mutated through a variety of other mechanisms such as DNA amplification, translocation, and deletion. Unlike synonymous or silent mutations, which do not cause amino acid changes, missense mutations are non-synonymous amino acid substitutions that are typically caused by single-base nucleotide point mutations. However, many random missense mutations are not expected to alter protein function due to plasticity built into many amino acid residues.

Advertisement

2. Cancer and the "two hits" of Knudson's hypothesis

Before proceeding into missense mutation in tumor suppressor gene we ought to introduce the "two hits" of Knudson's hypothesis. Alfred Knudson Jr in 1971 published his inspiring statistical analysis of the childhood cancer retinoblastoma where he found that retinoblastoma tend to be multifocal in familial cases and unifocal in sporadic presentation (Knudson A. G. Jr, 1971). Knudson postulated that patients with the familial form of the cancer would be born with one mutant allele and that all cells in that organ or tissue would be at risk, accounting for early onset and the multifocal nature of the disease. In contrast, sporadic tumors would develop only if a mutation occurred in both alleles within the same cell, and, as each event would be expected to occur with low frequency, most tumors would develop late in life and in a unifocal manner. His observations led him to propose a two-hit theory of carcinogenesis. The "two hits" of Knudson's hypothesis, which has proved true for many tumors, recognized that familial forms of cancer might hold the key to the identification of important regulatory elements known as tumor-suppressor genes (Ayerbes et al, 2008;.

Advertisement

3. Missense mutations in oncogenes and the tumor suppressor genes

Using the second generation sequencing approaches provided detailed information on the frequency and position of single point mutations as well as structural aberrations of cancer genomes such as small insertions and deletions, focal copy number alterations, and genomic rearrangementsm (Wood LD et al, 2007;. Jones S et al, 2008; Greenman C et al, 2007; Sjoblom T et al, 2006; Pleasance ED et al 2010a,b; Cancer Genome Atlas Research Network, 2008). The findings show that the complexity of each cancer genome is far greater than expected and that extensive variations exist between different cancer types as well as between different tumor samples of the same cancer type. Several recent studies have used the Catalogue Of Somatic Mutations In Cancer (COSMIC) database to discriminate oncogenes and the tumor suppressor genes by using the difference in their mutation patterns in order to understand oncogenesis and diagnose cancers (Forbes SA et al, 2008; Stehr H et al, 2011; Liu H, 2011). Such investigations at the systems level are currently being performed for many of oncogenes and the tumor suppressor genes as part of the Mutanom project (http://www.mutanom.org).

Stehr H et al study describes in a quantitative way, the opposing structural effects of cancer-associated missense mutations in oncogenes and tumor suppressors. Using COSMIC database (Forbes SA, 2008). Stehr H et al has assessed the effects of 1992 mutations cancer-associated mutations representing two common mechanisms through which tumorigenesis is initiated: via gain-of-function of oncogenes and loss-of-function of tumor suppressors (Vogelstein B et al, 1993). Then compared them to the effects of natural variants and randomized mutations. They focused on mechanisms of cancer mutations that have a consequence at the structural level. Another significant body of work has been published on consequences of mutations in a structural context (Ng PC, 2003, 2006; Ramensky V, et al, 2002; Wang Z et al, 2001; Karchin R et al, 2009). These studies differ in that either they focus on estimating the effects of individual mutations or they use different sets of disease mutations.

Studies of structural effects of mutations have found that disease mutations primarily occur in the protein core (Ramensky V, et al, 2002; Wang Z et al, 2001). This trend was confirmed only for the set of tumor suppressors. In contrast, core residues in oncogenes are significantly less often mutated than expected by chance. This is in agreement with Stehr H et al results for protein stability. Mutations located in the protein core are often destabilizing and result in loss-of-function. Thus, Stehr H et al data suggests that the loss-of-function of tumor suppressors is often caused by destabilization of the protein. They also suggested that specific mutations of functional sites that can either disable enzymatic activity and regulatory mechanisms or increase protein activity are often responsible for oncogene activation. Stehr H et al results show that the most frequently mutated types of functional sites in oncogenes are ATP and GTP binding sites and that the frequency of mutation is significantly higher than expected. This suggests that mutations of ATP and GTP binding sites are specific and common mechanisms of oncogene activation. Examples for such activating mutations near ATP binding sites have been described in the literature (Davies H et al, 2002; Shu HK et al, 1990, Jeffers M, et al, 1997).

Liu H et al investigated >120,000 mutation samples in 66 well-known tumor suppressor genes and oncogenes of the COSMIC database, and found a set of significant differences in mutation patterns (e.g., non-3n-indel, non-sense SNP and mutation hotspot) between them. They also developed indices to readily distinguish one from another and predict clearly the unknown oncogenesis genes as tumor suppressors (e.g., ASXL1, HNF1A and KDM6A) or oncogenes (e.g., FOXL2, MYD88 and TSHR). Based on their results, a third gene group was classified, which has a mutational pattern between tumor suppressors and oncogenes. The concept of the third gene group was thought to help in understanding gene function in different cancers or individual patients and to know the exact function of genes in oncogenesis.

Advertisement

4. The clinical of VHL disease

von Hippel-Lindau (VHL) disease (MIM 193300) is a dominantly inherited familial cancer syndrome. It is caused by mutations in the VHL tumor suppressor gene with an incidence of 1:31-36000 live births worldwide across all ethnic backgrounds, with similar prevalence in both genders (Maher et al., 1991; Maher, et al.2004). The prevalence however was shown to be higher in some population withtin the same ethnicity such as 1:39 000 in South-West Germany and 1:53 000 in Eastern England (Maher ER et al, 1991; Neumann H et al, 1991). VHL is characterized by marked age-dependent penetrance and phenotypic variability. The factors that affect the actual clinical expression and tumor formation, including age of onset, tissue and organ-specific lesions, severity of lesions, and recurrence, are unknown. VHL main clinical manifestations are:

4.1. Hemangioplastoms

Hemangioplastoms of the central nervous system (CNS) which are typically located in the cerebellum, but can also occur at the brainstem, spinal cord, and rarely, at the lumbosacral nerve roots and supratentorial (Neumann et al., 1995). Retinal or CNS hemangioblastomas are often the earliest manifestations of VHL disease and the most common, occurring in up to 80% of patients (Maher et al., 1990b; Melmon and Rosen, 1964; Weil et al., 2003). VHL-associated cerebellar hemangioblastomas are diagnosed at a mean age of 29–33 years, much earlier than sporadic cerebellar hemangioblastomas (Hes et al., 2000a, 2000b; Wanebo et al., 2003). These lesions are rarely malignant, but enlargement or bleeding within the CNS can result in neurological damage and death (Pavesi et al., 2008). A lower incidence of CNS hemangioblastomas has been documented in specific ethnic populations (12% Finland (Niemela M et al., 1999); 5% German (Zbar B et al., 1999). Patients with cerebellar haemangioblastomas typically present with symptoms of increased intracranial pressure and limb or truncal ataxia (depending on the precise location of the tumor). Wanebo et al. (2003) showed most CNS hemangioblastomas were associated with cysts that were often larger than other hemangioblastomas.

4.2. Pheochromocytoma

Pheochromocytomas are endocrine neoplasias with intra- or extra-adrenal gland lesions that appear histologically as an expansion of large chromaffin positive cells, derived from neural crest cells (Lee et al., 2005). Seven to 18% of VHL patients are afflicted with pheochromocytomas (Crossey et al., 1994a; Garcia et al., 1997). The absence or present of this phenotype will type the VHL into type 1or 2 (A,B,C), respectively (Woodward ER et al., 1997; Hofstra RMW et al., 1996). Untreated pheochromocytomas can result in hypertension and subsequent acute heart disease, brain edema, and stroke.

4.3. Clear cell renal cell carcinoma (RCC)

Clear cell renal cell carcinoma (RCC) occurs in up to 70% of patients with VHL and is a frequent cause of death. 70% of VHL patients have the risk of developing RCC by 60 years old (Maher et al., 1990b, 1991; Whaley et al., 1994), at an average age of 44 years versus the average age of 62 years, at which sporadic RCC develops in the general population (http://www.umd.be/VHL/W_VHL /clinic.shtml). Renal cysts are common in VHL patients as well; however, unlike the completely benign cysts in the general population, renal cysts in VHL patients might degenerate into RCC (Kaelin et al., 2004). However, it is unlikely that RCC in all VHL patients originates from cysts, or that all cysts will eventually become malignant. RCC often overproduces VEGF, and thus can be very vascular (Berse et al., 1992; Sato et al., 1994; Takahashi et al., 1994).

4.4. Others clinical manifestations

VHL patient can also have low-grade adenocarcinomas of the temporal bone, also known as endolymphatic sac tumors (ELST), pancreatic tumor, and epididymal or board ligament cystadenomas (Gruber et al., 1980; Neumann and Wiestler, 1991; Maher et al., 2004; Kaelin et al., 2007). ELST in VHL cases can be detected by MRI or CT imaging in up to 11% of patients (Manski TJ, et al., 1997). Although often asymptomatic, the most frequent clinical presentation is hearing loss (mean age 22 years), but tinnitus and vertigo also occur in many cases. In addition to the inherited risk for developing cancer, VHL patients develop cystic disease in various organs including the kidney, pancreas, and liver (Hough et al., 1994; Lubensky et al., 1998; Maher et al., 1990b; Maher, 2004).

Tumor growth commonly cycled between growth and quiescent phases. Patients with numerous tumors experienced growth and quiescent phases simultaneously, suggesting that a combination of acquired genetic lesions and hormonal activity influence tumor growth.

Advertisement

5. VHL clinical classification:

Molecular genetic mutation and phenotypic clustering has allowed development of a clinical classification, although intra-familial variability is well recognized.

As mentioned previously VHL disease can be classified into VHL Type 1 or Type 2 depending on the phenotype. Type 1 describes those with typical VHL manifestations such as emangioblastomas and RCC, but does not include pheochromocytomas. Once a pheochromocytoma occurs the classification becomes Type 2. Type 2, accounting for 7–20% of VHL kindreds, is further subdivided into: (2A) pheochromocytomas and other typical VHL manifestations except RCC, (2B) the full spectrum of VHL disease including pheochromocytomas, RCC, and other typical VHL manifestation, and Type (2C) identifies those with familial risk of isolated pheochromocytoma (Gross D et al, 1996; Martin R, et al., 1998), although there are some kindreds without identified VHL mutation raising the possibility of another genetic locus (Woodward ER et al, 1997; Crossey et al., 1994b; Garcia et al., 1997; Mulvihill et al., 1997).

Advertisement

6. Morbidity and Mortality of VHL

The morbidity of VHL disease depends on the organ system involved. For example, retinal hemangioblastomas can result in retinal detachment and/or blindness (Webster et al., 1999). Mortality is often due to either metastasis of RCC or complications of CNS hemangioblastomas (Filling-Katz et al., 1991; Maher et al., 1990b; Neumann et al., 1992); however, due to improved screening guidelines, life expectancy of VHL patients has improved.

Advertisement

7. VHL gene and pVHL function

The human VHL gene is a 10-kb region located on the short arm of chromosome 3 (3p25.3) (Richards et al., 1993) and consists of 3 exons (Kuzmin et al., 1995; Latif et al., 1993a, 1993b): Exon1 spans codons 1–113, exon 2 spans codons 114–154, and exon 3 spans codons 155–213. Two protein products are encoded by VHL: a 30-kDa full-length protein (p30, 213 amino acids, NM_000551.2 [variant 1 mRNA]) and a shorter protein product of 19-kDa (p19, 160 amino acids NM_198156.1 [variant 2 mRNA]), which is generated by alternative translation initiation at an internal methionine at position 54 (Blankenship et al., 1999). Although evolutionary conservation of VHL sequence is very strong over most of the pVHL19 sequence, the first 53 amino acids included in pVHL30 are less well conserved and functional studies suggest that the two pVHL isoforms have equivalent effects (Woodward ER et al, 2000; Iliopoulos O et al, 1998). The VHL mRNA and protein is widely expressed in both fetal and adult tissues (Richards FM et al., 1996; Corless CL et al., 1997) and can be found in all multicellular organisms examined to date without known similarity to other proteins (van M et al., 2001). Remarkable progress has been made in elaborating the function of pVHL and the role its inactivation plays in the pathophysiology of this disorder, including dysregulation of angiogenesis and tumor formation.

Given the lack of primary sequence homology to other proteins, the function of pVHL has been derived from studying pVHL interactors and associated proteins. Roles in oxygen-dependent angiogenesis, tumorigenesis, fibronectin matrix assembly and cytoskeleton organization, cell cycle control and cellular differentiation have been proposed. The N-terminal acidic domain of VHLp30 contains eight repetitions of a five-residue acidic repeat, which are absent in VHLp19. Phosphorylation of this acidic domain participates in tumor suppression and this domain binds the Kinesin-2 adaptor KAP3, thus mediating microtubule-binding (Lolkema et al., 2005, 2007). This domain is also responsible for binding metastasis suppressor Nm23H2, a protein known to regulate dynamin-dependent endocystosis (Hsu et al., 2006). Further downstream, the β-sheet domain (residues 63–154) binds HIF0a subunits at residues 65–117 and the α-helical domain (residues 155–192) binds the Elongin B and Elongin C (Elongin BC) complex at residues 158–184 (Feldman et al., 1999). Binding of pVHL to the Elongin BC is mediated by the chaperonin TRiC/ CCT. Elongin BC binding to pVHL requires TRiC, and VHL mutations causing defects in binding to Elongin BC are associated with VHL disease (Feldman et al., 1999). pVHL inactivation leads to an overexpression of hypoxia-inducible factor (HIF) and upregulation of its targets (vascular endothelial growth factor (VEGF), erythropoietin, transforming growth factor (TGF)-beta, alpha). Whether this is the sole etiologic factor causing characteristic VHL hemangioblastoma formation remains to be clarified. Evidence also suggests that pVHL inactivation alters fibronectin extracellular matrix formation, and that pVHL may participate in cellular differentiation and cell cycle control. Ongoing studies are directed at elaborating the biologic consequences that these pathways play in the angiogenesis and tumor formation central to VHL. Additionally, VHL protein has functions that are independent of HIF-1alpha and HIF-2alpha and are thought to be important for its tumor-suppressor action, assembly of the extracellular matrix, control of microtubule dynamics, regulation of apoptosis, and possibly stabilization of TP53 proteins (Frew IJ and Krek W. 2007).

Advertisement

8. Molecular genetics of VHL disease

Germline mutations, including large deletions/rearrangements, in the VHL gene, linked to 3p25-p26, are etiologic for virtually all VHL disease (Latif, F. et al., 1993; Stolle, C. et al., 1998; Zbar, B. et al., 1996). These VHL germline mutations may be also detected in patients with autosomal dominant familial non-syndromic phaeochromocytoma (Woodward ER et al., 1997; Neumann HP et al., 2002). Specific VHL missense mutations can cause an autosomal recessive form of polycythaemia without any evidence of VHL disease (AngSO et al., 2002; Gordeuk VR et al., 2004). Germ-line mutation confers genetic risk of tumor formation in concert with somatic second VHL allele loss or DNA methylation inactivation. However, somatic loss or inactivation of the wild-type vhl allele has been demonstrated in central nervous system (CNS) sporadic hemangioblastomas (Gnarra JR et al., 1994; Kanno H et al., 2000; Foster K et al., 1994; Herman JG et al 1994; Oberstrass J, et al., 1996; Tse J et al., 1997; Lee J-Y et al., 1998), in sporadic and VHL-associated renal cell carcinomas (RCCs) (Latif F et al, 1993; Shuin T et al., 1994; Phillips JL et al., 2001), pheochromocytoma (Bender BU et al., 2000; Linehan WM et al., 2001) and in endolymphatic sac tumors (ELSTs) (Vortmeyer AO et al., 2000).

More than 300 germline mutations have been identified in familial VHL. These occur throughout the coding region with only a few mutations appearing in multiple families (Zbar B et al., 1996; Beroud C et al., 1996). The new mutation rate has been estimated at between 3 and 20% (Latif F et al., 1993; Richard S et al., 1994; Schimke RN et al., 2000). Although decreased penetrance has been described (Maddock IF et al., 1994), comprehensive familial molecular data have not yet been reported to clarify this rate.

There has been limited correlation between specific mutation and phenotype, although some data on genotype-phenotype correlations have been reported (Neumann H et al., 1998; Hes F et al., 2000). Such correlations have revealed that certain missense mutations confer a high risk of pheochromocytoma (VHL type 1) whereas loss of pVHL through large deletions or nonsense-mediated decay appears to be incompatible with pheochromocytoma development (VHL type 2). [Chen et al., 1995; Cybulski et al., 2002; Glavac et al., 1996; Hes et al., 2000a, 2000b; Maher et al., 1996; Neumann and Bender, 1998; Ong et al., 2007; Zbar et al., 1996].

Interestingly, missense mutations causing amino acid changes on the surface of pVHL appear to have a higher risk for pheochromocytomas than missense mutations occurring deep within the protein; surface missense mutations also appear to have a higher risk for pheochromocytomas than deletions, nonsense, and frameshift mutations [Ong et al., 2007]. Thus, pheochromocytoma development appears to be related to an intact, but altered pVHL, which has seeded the hypothesis that these mutations may induce gain-of-function possibly through a dominant negative effect [Hoffman et al., 2001; Lee et al., 2005; Maher and Kaelin, 1997; Stebbins et al., 1999]. Nordstrom-O’Brien et al., 2010, analyzed 1548 VHL families and provided a wealth of data for genotype–phenotype correlations. They found 52% had missense mutations most frequently occurred at codons 65, 76, 78, 98, splice mutations at codon 155, 158, 161, 162, and 167. 13% had frameshift, 11% had nonsense, 6% had in-frame deletions/ insertions, 11% had large/complete deletions, and 7% had splice mutations. Mutations that predict absence of functional protein (deletion, frame-shift, nonsense, and splice) are associated in 96-97% of cases with type 1 phenotype and show an increased risk of RCC (including type 2b cases). This suggests that expressed dysfunctional protein may be required for pheochromocytoma formation. Missense mutations are associated with type 2 phenotype (hemangioblastoma and pheochromocytoma +/- RCC) in 69-98% of cases (Stolle C et al., 1998; Chen F et al., 1995; Zbar B et al., 1996). While Nordstrom-O’Brien et al., found 83.5% of VHL Type 2 families mainly had missense mutations. However, this is not as high as some studies, reporting up to 96% of those with pheochromocytomas to have missense mutations (Zbar et al., 1996). Nordstrom-O’Brien et al., found low percentage of VHL Type 2 families (0.5-7%) had other types of mutation such as nonsense, frameshift, splice, in-frame deletion/insertions, and partial deletions. The small percentage of nonsense and partial deletions along with the absence of complete deletions supports theories that an intact though altered pVHL is associated with pheochromocytomas. Stratifying missense mutations into those that resulted in substitution of a surface amino acid and those that disrupted structural integrity demonstrated that surface amino acid substitutions conferred a higher pheochromocytoma risk (Ong KR et al., 2007). Although loss of heterozygosity has been reported in endolymphatic sac tumors (ELST) tumors (Kawahara N et al., 1999; Vortmeyer AO et al., 1997) no predominant mutation has been identified.

It may be difficult, however, to predict functional biologic consequences from specific point mutations without direct functional assays as reported in recent RCC in-vitro mutation panel studies.

The recent characterization of the VHL protein crystal structure might suggests possible functional consequences of specific mutations. If we focus on the structure of the pVHL we can predict the effect of the mutation on the functionality of the pVHL and therefore the phenotype resulted. Mutation-specific dysfunction may depend on protein destabilization, altered interactor binding at the various pVHP binding domains or potential alteration in binding to other factors involved in tumor suppressor/activator activity. pVHL has two domains: an amino-terminal domain rich in β-sheet (the β-domain) and a smaller carboxyterminal α-helical domain (the α-domain). A large portion of the α-domain surface interacts with Elongin C, which binds to other members (e.g., Elongin B, Cul2, and Rbx1) of an SCF-like E3 ubiquitin-protein ligase complex as mentioned earlier. Obviously, loss of function VHL mutations prevents Elongin C binding and target ubiquitylation (Clifford et al., 2001). The β-domain on the other side has a macromolecular binding site targets the HIF-1α and HIF-2α regulatory subunits for proteasomal degradation. Whereas Type 1 and Type 2B mutations impair pVHL binding to Elongin C, Type 2A mutations map to the β-domain HIF-binding site and do not affect the ability of pVHL to bind Elongin C (Clifford et al., 2001). Therefore, classifying missense substitutions according to their predicted effect on pVHL structure enhances the ability to predict pheochromocytoma risk (Ong KR et al., 2007)

Nordstrom-O’Brien et al 2010 suggested that increased identification of new mutations and new patients with previously described mutations gives momentum to the search for the exact role of pVHL in its normal and mutated form. Understanding such functions and its association with specific mutations allows for identification of disease risks in individual patients. Such insight will offer improved diagnostics, surveillance, and treatment of VHL patients (Nordstrom-O’Brien et al., 2010).

Ongoing delineation of clinical subtypes may allow for better genotype-phenotype correlations, prediction of clinical progression and molecular mutation-directed clinical management. There is significant intra-familial difference in clinical expressivity and as of yet limited knowledge about modifiers of this phenotypic variation (Webster AR, et al, 1998). Prediction of the clinical course in any one patient based on molecular data is therefore difficult.

References

  1. 1. Ang SO, Chen H, HirotaK et al: Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 2002; 32: 614-621.
  2. 2. AyerbesV. M.GallegoA. G.DSPradoFonseca. J. P.CampeloG. R.AparicioA. L. M.Origin of renal cell carcinomasClin Transl Oncol. 2008Nov;1011697712
  3. 3. BenderB. U.GutscheM.GlaskerS.et al.Differential genetic alterations in von Hippel-Lindau syndrome-associated and sporadic pheochromocytomas.J Clin Endocrinol Metab 20008545684574
  4. 4. BeroudC.JolyD.GallouC.et al.Software and database for the analysis of mutation in VHL gene [www.umd.necker.fr:2005]. Nucleic Acids Res 199826256258
  5. 5. BerseB.BrownL. F.Van de WaterL.DvorakH. F.SengerD. R.Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell 19923211220
  6. 6. BlankenshipC.NaglichJ. G.WhaleyJ. M.SeizingerB.KleyN.Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity.Oncogene19991815291535
  7. 7. Cancer Genome Atlas Research Network: Comprehensive genomic characterization defines human glioblastoma genes and core pathways.Nature 200845510611068
  8. 8. ChenF.KishidaT.YaoM.et al.Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype.Hum Mutat 199556675
  9. 9. Clifford SC, Cockman ME, Smallwood AC, Mole DR, Woodward ER, Maxwell PH, Ratcliffe PJ, Maher ER.Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease.Hum Mol Genet 20011010291038
  10. 10. Corless CL, Kibel AS, Iliopoulos O et al: Immunostaining of the von Hippel-Lindau gene product in normal and neoplastic human tissues. Hum Path 1997; 28: 459-464.
  11. 11. CrosseyP. A.FosterK.RichardsF. M.MEPhippsLatif. F.ToryK.JonesM. H.BentleyE.KumarR.LermanM. I.ZbarB.AffaraN. A.MAFerguson-SmithMaher. E. R.Molecular genetic investigations of the mechanism of tumourigenesis in von Hippel-Lindau disease: analysis of allele loss in VHL tumours.Hum Genet 1994a935358
  12. 12. CrosseyP. A.RichardsF. M.FosterK.GreenJ. S.ProwseA.LatifF.LermanM. I.ZbarB.AffaraN. A.MAFerguson-SmithMaher. E. R.Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet 1994b313031308
  13. 13. CybulskiC.KrzystolikK.MurgiaA.GorskiB.et al.Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL geneJ Med Genet 2002E38.
  14. 14. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, et al: Mutations of the BRAF gene in human cancer. Nature 2002; 417:949-954.
  15. 15. FeldmanD. E.ThulasiramanV.FerreyraR. G.FrydmanJ.Formation of the VHLelongin BC tumor suppressor complex is mediated by the chaperonin TRiC.Mol Cell 1999410511061
  16. 16. Filling-KatzM. R.ChoykeP. L.OldfieldE.CharnasL.PatronasN. J.GlennG. M.GorinM. B.MorganJ. K.LinehanW. M.SeizingerB. R.ZbarB.Central nervous system involvement in Von Hippel-Lindau disease.Neurology1991414146
  17. 17. Forbes SA, Bhamra G, Bamford S, Dawson E, Kok C, Clements J, Menzies A, Teague JW, Futreal PA, Stratton MR: The Catalogue of Somatic Mutations in Cancer (COSMIC). Curr Protoc Hum Genet 2008; Chapter 10, Unit 10 11.
  18. 18. FosterK.ProwseA.van denBerg. A.et al.Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet 1994321692173
  19. 19. FrewI. J.KrekW.Multitaskingby. p. V. H. L.intumour.suppressionCurr Opin Cell Biol 200719685690
  20. 20. Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R, Rahman N, Stratton MR. A census of human cancer genes. Nat Rev Cancer. 2004;4(3):177-83.
  21. 21. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, et al: Patterns of somatic mutation in human cancer genomes. Nature 2007; 446:153-158.
  22. 22. GarciaA.Matias-GuiuX.CabezasR.ChicoA.PratJ.BaigetM.De LeivaA.Molecular diagnosis of von Hippel-Lindau disease in a kindred with a predominance of familial phaeochromocytoma.Clin Endocrinol (Oxf) 199746359363
  23. 23. GlavacD.NeumannH. P.WittkeC.JaenigH.MasekO.StreicherT.PauschF.EngelhardtD.PlateK. H.HoflerH.ChenF.ZbarB.BrauchH.Mutations in the VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe.Hum Genet 199698271280
  24. 24. GnarraJ. R.ToryK.WengY.et al.Mutations of the VHL tumour suppressor gene in renal carcinoma.Nat Genet 199478590
  25. 25. Gordeuk VR, Sergueeva AI, Miasnikova GY et al: Congenital disorder of oxygen-sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors.Blood 200410339243932
  26. 26. GrossD.AvishaiN.MeinerV.et al.Familial pheochromocytoma associated with a novel mutation in the von Hippel-Lindau geneJ Clin Endocrinol Metab 199681147149
  27. 27. Gruber MB, Healey GB, Toguri AG, Warren MM.Papillary cystadenoma of epididymis: component of von Hippel-Lindau syndrome.Urology198016305306
  28. 28. HermanJ. G.LatifF.WengY.et al.Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinomaProc Natl Acad Sci USA 19949197009704
  29. 29. HesF.ZewaldR.PeetersT.SijmonsR.LinksT.VerheijJ.MatthijsG.LeguisE.MortierG.van der TorrenK.RosmanM.LipsC.PearsonP.van der LuijtR.Genotype-phenotype correlations in families with deletions in the von Hippel-Lindau (VHL) gene. Hum Genet 2000a106425431
  30. 30. HesF. J.Mc KeeS.MJTaphoornRehal. P.van Der LuijtR. B.Mc MahonR.van Der SmagtJ. J.DowD.ZewaldR. A.WhittakerJ.LipsC. J.MacDonald. F.PearsonP. L.MaherE. R.Cryptic von Hippel-Lindau disease: germline mutations in patients with haemangioblastoma only. J Med Genet 2000b37939943
  31. 31. MAHoffmanOhh. M.YangH.KlcoJ. M.IvanM.Kaelin JrW. G.von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF.Hum Mol Genet 20011010191027
  32. 32. HofstraR. M. W.StelwagenT.StulpR. P.et al.Extensive mutation screening of RET in sporadic medullary thyroid carcinoma and of RET and VHL in sporadic pheochromocytoma reveals involvement of these genes in only a minority of cases. J Clin Endocrinol Metab 1996
  33. 33. Hough DM, Stephens DH, Johnson CD, Binkovitz LA.Pancreatic lesions in von Hippel-Lindau disease: prevalence, clinical significance, and CT findings.AJRAm J Roentgenol 199416210911094
  34. 34. HsuT.AderethY.KoseN.DammaiV.Endocytic function of von Hippel-Lindau tumor suppressor protein regulates surface localization of fibroblast growth factor receptor 1 and cell motility.J Biol Chem 20062811206912080
  35. 35. Iliopoulos O, Ohh M, Kaelin Jr WG: pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation. Proc Natl Acad Sci USA 1998; 95: 11661-1166.
  36. 36. Ivan M, KaelinWG.The vonHippel-Lindau tumor suppressor protein. Curr Opin Genet Dev 2001; 11:27-34.
  37. 37. Jeffers M, Schmidt L, Nakaigawa N, Webb CP, Weirich G, Kishida T, Zbar B, VandeWoude GF: Activating mutations for the met tyrosine kinase receptor in human cancer. Proc Natl Acad Sci USA 1997; 94:11445-11450.
  38. 38. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, et al: Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science (New York, NY) 2008; 321:1801-1806.
  39. 39. Kaelin Jr WG.The von Hippel-Lindau tumor suppressor gene and kidney cancer.Clin Cancer Res 2004Pt 2):6290S EOF5S EOF
  40. 40. Kaelin WG. Von Hippel-Lindau disease.Annu Rev Pathol 20072145173
  41. 41. KannoH.SaljooqueF.YamamotoI.et al.Role of the von Hippel-Lindau tumor suppressor protein during neuronal differentiation.Cancer Res 20006028202824
  42. 42. Karchin R: Next generation tools for the annotation of human SNPs. Brief Bioinform 2009; 10:35-52.
  43. 43. Kawahara N, Kume H, Ueki K, et al. VHL gene inactivation in an endolymphatic sac tumor associated with von Hippel-Lindau disease. Neurology 1999; 53:208-210.
  44. 44. KnudsonA. G.Jr Mutation and cancer: statistical study of retinoblastoma. Proc. Natl. Acad. Sci. USA 197168820823
  45. 45. KuzminI.DuhF. M.LatifF.GeilL.ZbarB.LermanM. I.Identification of the promoter of the human von Hippel-Lindau disease tumor suppressor gene.Oncogene19951011218594
  46. 46. Latif F, Duh FM, Gnarra J, Tory K, Kuzmin I, Yao M, Stackhouse T, Modi W, Geil L, Schmidt L, Li H, Orcutt ML, Maher E, Richards F, Phipps M, Ferguson-Smith M, Le Paslier D, Linehan WM, Zbar B, Lerman MI. von Hippel-Lindau syndrome: cloning and identification of the plasma membrane Ca(11)-transporting ATPase isoform 2 gene that resides in the von Hippel-Lindau gene region. Cancer Res 1993a;53:861-867.
  47. 47. Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, and many others. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993b; 260:1317-1320.
  48. 48. Lee J-Y, Dong S-M, Park W-S, et al.Loss of heterozygosity and somatic mutations of the VHL tumor suppressor gene in sporadic cerebellar hemangioblastomas.Cancer Res 199858504508
  49. 49. LeeS.NakamuraE.YangH.WeiW.MSLinggiSajan. M. P.FareseR. V.FreemanR. S.BDCarterKaelin.Jr SchlisioW. G.S.Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer.Cancer Cell2005155167
  50. 50. LinehanW. M.EisenhoferG.MMWaltherGoldstein.DSRecent advances in genetics, diagnosis, localization and treatment of pheochromocytoma. Ann Intern Med 2001134315329
  51. 51. LiuH.XingY.YangS.TianD.Remarkable difference of somatic mutation patterns between oncogenes and tumor suppressor genesOncol Rep. 2011266153946
  52. 52. LolkemaM. P.GervaisM. L.SnijckersC. M.HillR. P.GilesR. H.EEVoestOhh. M.Tumor suppression by the von Hippel-Lindau protein requires phosphorylation of the acidic domain.J Biol Chem 2005802220522211
  53. 53. LolkemaM. P.MansD. A.SnijckersC. M.van NoortM.van BeestM.EEVoestGiles. R. H.The von Hippel-Lindau tumour suppressor interacts with microtubules through kinesin-2FEBS Lett 200758145714576
  54. 54. LubenskyI. A.PackS.AultD.VortmeyerA. O.LibuttiS. K.ChoykeP. L.MMWaltherLinehan. W. M.ZhuangZ.Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients: histopathological and molecular genetic analysisAm J Pathol 1998153223231
  55. 55. Maddock IF, Moran A, Maher ER, et al. A genetic register for von Hippel-Lindau disease. J Med Genet 1996; 33:120-127.
  56. 56. Maher ER. Von Hippel-Lindau disease.Curr Mol Med 20044833842
  57. 57. Maher ER, Iselius L, Yates JR, Littler M, Benjamin C, Harris R, Sampson J,Williams A, Ferguson-Smith MA, Morton N. Von Hippel-Lindau disease: a genetic study. J Med Genet 1991; 28:443-447
  58. 58. Maher ER, Kaelin Jr WG. von Hippel-Lindau disease. Medicine (Baltimore)199776381391
  59. 59. Maher ER, Webster AR, Richards FM, Green JS, Crossey PA, Payne SJ, Moore AT.Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations.J Med Genet 199633328332
  60. 60. MaherE. R.YatesJ. R.HarriesR.BenjaminC.HarrisR.MooreA. T.MAFerguson-SmithClinical features and natural history of von Hippel-Lindau disease.Q J Med 1990b7711511163
  61. 61. Manski TJ, Heffner DK, Glenn GM et al: Endolymphatic sac tumors-A source of morbid hearing loss in von Hippel-Lindau disease.Jama-Journal of the American Medical Association 199727714611466
  62. 62. MartinR.HockeyA.WalpoleI.et al.Variable penetrance of familial pheochromocytoma associated with the von Hippel-Lindau gene mutation, S68WMutations in brief 150Online Hum Mutat 199871 EOF
  63. 63. Melmon KL, Rosen SW. Lindau’s disease.Review of the literature and study of a large kindred. Am J Med 196436595617
  64. 64. MulvihillJ. J.FerrellR. E.CartyS. E.TishermanS. E.ZbarB.Familial pheochromocytoma due to mutant von Hippel-Lindau disease gene.Arch Intern Med 199715713901391
  65. 65. NeumannH.BenderB.Genotype-phenotype correlations in von Hippel-Lindau disease.J Intern Med 1998541 EOF5 EOF
  66. 66. Neumann HP, Wiestler OD.Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus.Lancet199133710521054
  67. 67. Neumann HP, Bausch B, McWhinney SR et al: Germ-line mutations in nonsyndromic Phaeochromocytoma. N Engl J Med 2002; 346: 1459-6621.
  68. 68. NeumannH. P.EngC.MulliganL. M.GlavacD.ZaunerI.BAPonderCrossey. P. A.MaherE. R.BrauchH.Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type IIJAMA199527411491151
  69. 69. NeumannH. P.EggertH. R.ScheremetR.SchumacherM.MohadjerM.WakhlooA. K.VolkB.HettmannspergerU.RieglerP.SchollmeyerP.Central nervous system lesions in von Hippel-Lindau syndrome.J Neurol Neurosurg Psychiatry 199255898901
  70. 70. Neumann HP, Wiestler OD.Clustering of features and genetics of von Hippel-Lindau syndrome.Lancet1991258 EOF
  71. 71. NgP. C.HenikoffS.Predicting the effects of amino acid substitutions on protein function.Annu Rev Genomics Hum Genet 200676180
  72. 72. Ng PC, Henikoff S: SIFT: Predicting amino acid changes that affect protein function. Nucleic acids research 2003; 31:3812-3814.
  73. 73. NiemelaM.LemetaS.SummanenP.et al.Long-term prognosis of haemangioblastoma of the CNS: impact of von Hippel-Lindau disease.Acta Neurochir 19991147 EOF56 EOF
  74. 74. Nordstrom-O’Brien M, van der Luijt RB, van Rooijen E, van den Ouweland AM, Majoor-Krakauer DF, Lolkema MP, van Brussel A, Voest EE, Giles RH.Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010; 31(5):521-37.
  75. 75. OberstrassJ.ReifenbergerG.ReifenbergerJ.et al.Mutations of the von Hippel-Lindau tumour suppressor gene in capillary haemangioblastomas of the central nervous system. J Pathol 1996179151156
  76. 76. OngK. R.WoodwardE. R.KillickP.LimC.MacdonaldF.MaherE. R.Genotype-phenotype correlations in von Hippel-Lindau disease.Hum Mutat 200728143149
  77. 77. PavesiG.FelettiA.BerlucchiS.OpocherG.MartellaM.MurgiaA.ScienzaR.Neurosurgical treatment of von Hippel-Lindau-associated hemangioblastomas: benefits, risks and outcome.J Neurosurg Sci 2008522936
  78. 78. PhillipsJ. L.BMGhadimiWangsa. D.et al.Molecular cytogenetic characterization of early and late renal cell carcinomas in von Hippel-Lindau disease.GenesChromosomes Cancer 20013119
  79. 79. Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, Varela I, Lin ML, Ordonez GR, Bignell GR, et al: A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 2010a; 463:191-196.
  80. 80. Pleasance ED, Stephens PJ, O’Meara S, McBride DJ, Meynert A, Jones D, Lin ML, Beare D, Lau KW, Greenman C, et al: A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 2010b; 463:184-190.
  81. 81. Ramensky V, Bork P, Sunyaev S: Human non-synonymous SNPs: server and survey. Nucleic acids research 2002; 30:3894-3900.
  82. 82. RichardsF. M.MaherE. R.LatifF.MEPhippsTory. K.LushM.CrosseyP. A.OostraB.EnbladP.GustavsonK. H.GreenJ.TurnerG.YatesJ. R. W.LinehanW. M.AffaraN. A.LermanM.ZbarB.MAFerguson-SmithDetailed genetic mapping of the von Hippel-Lindau disease tumour suppressor gene.J Med Genet 199330104107
  83. 83. Richards FM, Payne SJ, Zbar B et al: Molecular Analysis of De-Novo Germline Mutations in the von Hippel-Lindau Disease Gene. Hum Mol Gen 1995; 4:2139-2143.
  84. 84. Richards FM, Schofield PN, Fleming S: Expression of the von Hippel-Lindau disease tumour suppressor gene during human embryogenesis. Hum Mol Gen 1996; 5: 639-644.
  85. 85. RichardS.ChauveauD.ChretienY.et al.Renal lesions and pheochromocytoma in von Hippel-Lindau disease.Adv Nephrol 199423127
  86. 86. SatoK.TeradaK.SugiyamaT.TakahashiS.SaitoM.MoriyamaM.KakinumaH.SuzukiY.KatoM.KatoT.Frequent overexpression of vascular endothelial growth factor gene in human renal cell carcinoma.Tohoku J Exp Med 1994173355360
  87. 87. Schimke RN, Collins D, Stolle CA. Von Hippel-Lindau syndrome. In: GeneClinics: clinical genetic information resource; www.geneclinics.org/profiles/vhl.
  88. 88. Shu HK, Pelley RJ, Kung HJ: Tissue-specific transformation by epidermal growth factor receptor: a single point mutation within the ATP-binding pocket of the erbB product increases its intrinsic kinase activity and activates its sarcomagenic potential.Proc Natl Acad Sci USA 19908791039107
  89. 89. ShuinT.KondoK.TorigoeS.et al.Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas.Cancer Res 19945428522855
  90. 90. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, et al: The consensus coding sequences of human breast and colorectal cancers. Science 2006; 314:268-274.
  91. 91. Stebbins CE, Kaelin Jr WG, Pavletich NP.Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function.Science 1999284455461
  92. 92. StehrH.JangS. H.DuarteJ. M.WierlingC.LehrachH.LappeM.BMLangeThe structural impact of cancer-associated missense mutations in oncogenes and tumor suppressors.Mol Cancer. 201154 EOF
  93. 93. StolleC.GlennG.ZbarB.et al.Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene.Hum Mutat 199812417423
  94. 94. TakahashiA.SasakiH.KimS. J.TobisuK.KakizoeT.TsukamotoT.KumamotoY.SugimuraT.TeradaM.Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis.Cancer Res 19945442334237
  95. 95. TseJ.WongJ.Lo-WK.et al.Molecular genetic analysis of the von Hippel-Lindau disease tumor suppressor gene in familial and sporadic cerebellar hemangioblastomasAm J Clin Pathol 1997107459466
  96. 96. Vogelstein B, Kinzler KW: The multistep nature of cancer. Trends Genet 1993; 9:138-141.
  97. 97. Vortmeyer AO, Huang SC, Koch CA, et al.Somatic von Hippel-Lindau gene mutations detected in sporadic endolymphatic sac tumors.Cancer Res 20006059635965
  98. 98. VortmeyerA. O.ChooD.PackS. D.et al.Von Hippel-Lindau disease gene alterations associated with endolymphatic sac tumor.J Natl Cancer Inst 199789970972
  99. 99. Wanebo JE, Lonser RR, Glenn GM, Oldfield EH.The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease.J Neurosurg 2003988294
  100. 100. WangZ.MoultJ. S. N.Psprotein.structurediseaseHuman.Mutation2001
  101. 101. Webster AR, Maher ER, Moore AT.Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation.Arch Ophthalmol 1999117371378
  102. 102. Webster AR, Richards FM, MacRonald FE, et al.An analysis of phenotypic variation in the familial cancer syndrome von Hippel-Lindau disease: evidence for modifier effects.Am J Hum Genet 19986310251035
  103. 103. Weil RJ, Lonser RR, DeVroom HL, Wanebo JE, Oldfield EH.Surgical management of brainstem hemangioblastomas in patients with von Hippel-Lindau disease.J Neurosurg 20039895105
  104. 104. WhaleyJ. M.NaglichJ.GelbertL.HsiaY. E.LamiellJ. M.GreenJ. S.CollinsD.NeumannH. P.LaidlawJ.LiF. P.Klein-SzantoA. J. P.SeizingerB. R.KleyN.Germ-line mutations in the von Hippel-Lindau tumor-suppressor gene are similar to somatic von Hippel-Lindau aberrations in sporadic renal cell carcinomaAm J Hum Genet 19945510921102
  105. 105. Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, et al: The genomic landscapes of human breast and colorectal cancers. Science 2007; 318:1108-1113.
  106. 106. Woodward ER, Buchberger A, Clifford SC et al: Comparative sequence analysis of the VHL tumor suppressor gene. Genomics 2000; 65: 253-265.
  107. 107. WoodwardE. R.EngC.Mc MaonR.et al.Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL.Hum Mol Genet 1997610511056
  108. 108. WoodwardE. R.EngC.Mc MaonR.et al.Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHLHum Mol Genet 1997610511056
  109. 109. Woodward ER, Eng C, McMahon R et al: Genetic predisposition to phaeochromocytoma: Analysis of candidate genes GDNF, RET and VHL. Hum Mol Genet 1997; 6: 1051-1056.
  110. 110. ZbarB.KaelinW.MaherE.et al.Third International Meeting on von Hippel-Lindau disease.Cancer Res 19995922512253
  111. 111. ZbarB.KishidaF.Chenet.alGermlinemutations in the von Hippel-Lindau disease (VHL) gene in families from North American, Europe and Japan. Hum. Mutat. 19968348357
  112. 112. ZbarB.KishidaT.ChenF.et al.Germline mutations in the von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 1996
  113. 113. ZbarB.KishidaT.ChenF.SchmidtL.MaherE. R.RichardsF. M.CrosseyP. A.WebsterA. R.AffaraN. A.MAFerguson-SmithBrauch. H.Glavac D,
  114. 114. NeumannH. P.TishermanS.MulvihillJ. J.GrossD. J.ShuinT.WhaleyJ.SeizingerB.KleyN.OlschwangS.BoissonC.RichardS.LipsC. H.LermanM.LinehanW. M.Germline mutations in the Von Hippel-Lindaudisease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 19968348357

Written By

Suad AlFadhli

Submitted: 25 May 2011 Published: 12 October 2012