Reviewed, UniProtKB/Swiss-Prot P40337 (VHL_HUMAN)

Names and origin

Protein names

Recommended name:
    Von Hippel-Lindau disease tumor suppressor
Alternative name(s):
    pVHL
    Protein G7

Gene names

Name:

VHL

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	213 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Seems to act as target recruitment subunit in the E3 ubiquitin ligase complex and recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic conditions. Involved in transcriptional repression through interaction with HIF1A, HIF1AN and histone deacetylases. Ref.11 Ref.13
Pathway	Protein modification; protein ubiquitination.
Subunit structure	Component of the VCB (VHL-Elongin BC-CUL2) complex; this complex acts as a ubiquitin-ligase E3 and directs proteosome-dependent degradation of targeted proteins. Interacts with CUL2; this interaction is dependent on the integrity of the trimeric VBC complex. Interacts (via the beta domain) with HIF1A (via the NTAD domain); this interaction mediates degradation of HIF1A in normoxia and, in hypoxia, prevents ubiqitination and degradation of HIF1A by mediating hypoxia-induced translocation to the nucleus, a process which requires a hypoxia-dependent regulatory signal. Interacts with RNF139 and UBP33. Interacts with PHF17. Ref.13 Ref.8 Ref.10 Ref.12 Ref.15 Ref.16 Ref.17 Ref.18
Subcellular location	Isoform 1: Cytoplasm. Membrane; Peripheral membrane protein. Nucleus. Note: Found predominantly in the cytoplasm and with less amounts nuclear or membrane-associated. Ref.11 Isoform 3: Cytoplasm. Nucleus. Note: Equally distributed between the nucleus and the cytoplasm but not membrane-associated. Ref.11
Tissue specificity	Expressed in the adult and fetal brain and kidney.
Domain	The Elongin BC complex binding domain is also known as BC-box with the consensus [APST]-L-x(3)-C-x(3)-[AILV].
Involvement in disease	Defects in VHL are a cause of pheochromocytoma [MIM:171300]. The pheochromocytomas are catecholamine-producing, chromaffin tumors that arise in the adrenal medulla in 90% of cases. In the remaining 10% of cases, they develop in extra-adrenal sympathetic ganglia and may be referred to as "paraganglioma." Pheochromocytoma usually presents with hypertension. Approximately 10% of pheochromocytoma is hereditary. The genetic basis for most cases of non-syndromic familial pheochromocytoma is unknown. Ref.36 Ref.41 Ref.43 Defects in VHL are the cause of von Hippel-Lindau disease (VHLD) [MIM:193300]. VHLD is a dominantly inherited familial cancer syndrome characterized by the development of retinal angiomatosis, cerebellar and spinal hemangioblastoma, renal cell carcinoma (RCC), phaeochromocytoma and pancreatic tumors. VHL type 1 is without pheochromocytoma, type 2 is with pheochromocytoma. VHL type 2 is further subdivided into types 2A (pheochromocytoma, retinal angioma, and hemangioblastomas without renal cell carcinoma and pancreatic cyst) and 2B (pheochromocytoma, retinal angioma, and hemangioblastomas with renal cell carcinoma and pancreatic cyst). VHL type 2C refers to patients with isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma. The estimated incidence is 3/100000 births per year and penetrance is 97% by age 60 years. Ref.12 Ref.1 Ref.24 Ref.25 Ref.26 Ref.27 Ref.28 Ref.29 Ref.30 Ref.31 Ref.32 Ref.33 Ref.34 Ref.35 Ref.37 Ref.38 Ref.39 Ref.46 Defects in VHL are the cause of erythrocytosis familial type 2 (ECYT2) [MIM:263400]; also called VHL-dependent polycythemia or Chuvash type polycythemia. ECYT2 is an autosomal recessive disorder characterized by an increase in serum red blood cell mass, hypersensitivity of erythroid progenitors to erythropoietin, increased erythropoietin serum levels, and normal oxygen affinity. Patients with ECYT2 carry a high risk for peripheral thrombosis and cerebrovascular events. Ref.42 Ref.45 Defects in VHL are a cause of renal cell carcinoma type 1 (RCC1) [MIM:144700]; also called hypernephroma or adenocarcinoma of kidney. Familial renal cell carcinoma syndromes form a group of diseases characterized by a predisposition to development of renal cell carcinomas (RCCs) with various histological subtypes. Ref.40

Ontologies

Keywords
Biological process	Cell cycle Ubl conjugation pathway
Cellular component	Cytoplasm Membrane Nucleus
Coding sequence diversity	Alternative initiation Alternative splicing Polymorphism
Disease	Congenital erythrocytosis Disease mutation
Domain	Repeat
Molecular function	Anti-oncogene
Technical term	3D-structure
Gene Ontology (GO)
Biological process	anti-apoptosis Ref.17 Non-traceable author statement. Source: UniProtKB cell cycle Inferred from electronic annotation. Source: UniProtKB-KW cell morphogenesis Ref.17 Non-traceable author statement. Source: UniProtKB modification-dependent protein catabolic process Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of cell cycle Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of cell proliferation Ref.10 Traceable author statement. Source: ProtInc negative regulation of transcription from RNA polymerase II promoter Traceable author statement. Source: ProtInc positive regulation of cell differentiation Ref.17 Non-traceable author statement. Source: UniProtKB positive regulation of transcription Inferred from mutant phenotype. Source: UniProtKB protein stabilization Ref.17 Non-traceable author statement. Source: UniProtKB protein ubiquitination Ref.17 Inferred from mutant phenotype. Source: UniProtKB response to stress Ref.17 Non-traceable author statement. Source: UniProtKB
Cellular component	cytosol Traceable author statement. Source: ProtInc endoplasmic reticulum Ref.17 Non-traceable author statement. Source: UniProtKB membrane Inferred from electronic annotation. Source: UniProtKB-SubCell mitochondrion Ref.17 Non-traceable author statement. Source: UniProtKB nucleus Traceable author statement. Source: ProtInc
Molecular function	transcription factor binding Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
APRT	P07741	1	EBI-301246,EBI-1047565
ATXN2	Q99700	1	EBI-301246,EBI-697691
CAB39	Q9Y376	1	EBI-301246,EBI-306905
CCDC59	Q9P031	1	EBI-301246,EBI-1047110
CCDC82	Q8N4S0	1	EBI-301246,EBI-1048482
CDK2	P24941	1	EBI-301246,EBI-375096
CHMP2B	Q9UQN3	1	EBI-301246,EBI-718324
CNTF	P26441	1	EBI-301246,EBI-1050897
COPS5	Q92905	1	EBI-301246,EBI-594661
CSTB	P04080	1	EBI-301246,EBI-1051966
CSTF3	Q12996	1	EBI-301246,EBI-1056775
CUL2	Q13617	1	EBI-301246,EBI-456179
DGKI	O75912	1	EBI-301270,EBI-1765520
DGKI	O75912	1	EBI-301246,EBI-1765520
FSCN1	Q16658	1	EBI-301246,EBI-351076
HAS1	Q92839	1	EBI-301246,EBI-1052423
HIF1A	Q16665	1	EBI-301246,EBI-447269
HIST1H2BC	P62807	1	EBI-301246,EBI-354552
IMPDH2	P12268	1	EBI-301246,EBI-353389
KNTC1	P50748	1	EBI-301246,EBI-1001245
MCC	P23508	1	EBI-301246,EBI-307531
MOBKL3	Q9Y3A3	1	EBI-301246,EBI-713935
MRLC3	P19105	1	EBI-301246,EBI-354418
NEDD8	Q15843	1	EBI-301246,EBI-716247
PAPSS2	O95340	1	EBI-301246,EBI-1053912
PCMT1	P22061	1	EBI-301246,EBI-353343
PFAS	O15067	1	EBI-301246,EBI-1052653
PIN1	Q13526	1	EBI-301246,EBI-714158
PPIB	P23284	1	EBI-301246,EBI-359252
PSMB1	P20618	1	EBI-301246,EBI-372273
PSMB3	P49720	1	EBI-301246,EBI-603340
PSMD13	Q9UNM6	1	EBI-301246,EBI-356070
PTGES3	Q15185	1	EBI-301246,EBI-1049387
RAB1B	Q9H0U4	1	EBI-301246,EBI-1045214
RAB7A	P51149	1	EBI-301246,EBI-1056089
RASGRP1	O95267	1	EBI-301246,EBI-1054956
RBX1	P62877	1	EBI-301246,EBI-398523
RHOC	P08134	1	EBI-301246,EBI-747589
RNF139	Q8WU17	1	EBI-301246,EBI-1551681
RPS9	P46781	1	EBI-301246,EBI-351206
STK16	O75716	1	EBI-301246,EBI-1046308
TAGLN2	P37802	1	EBI-301246,EBI-1056740
TARS	P26639	1	EBI-301246,EBI-1042683
TCEB1	Q15369	1	EBI-301246,EBI-301231
TCEB2	Q15370	1	EBI-301246,EBI-301238
TGFB1I1	O43294	1	EBI-301246,EBI-1051449
TPT1	P13693	1	EBI-301246,EBI-1783169
TXN	Q5T937	1	EBI-301246,EBI-1042712

Alternative products

This entry describes 3 isoforms produced by alternative splicing and alternative initiation. [Align] [Select]

Isoform 1 (identifier: P40337-1)

Also known as: VHL30; VHLp24(MPR);

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Note: Found predominantly in the cytoplasm and with less amounts nuclear or membrane-associated. Ref.11 Major isoform.

Isoform 2 (identifier: P40337-2)

The sequence of this isoform differs from the canonical sequence as follows:
     114-154: Missing.

Isoform 3 (identifier: P40337-3)

Also known as: VHL19; VHLp18(MEA);

The sequence of this isoform differs from the canonical sequence as follows:
     1-53: Missing.

Note: Equally distributed between the nucleus and the cytoplasm but not membrane-associated. Ref.11 Produced by alternative initiation at Met-54 of isoform 1.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 213

213

Von Hippel-Lindau disease tumor suppressor

PRO_0000065809

Regions

Repeat

14 – 18

5

1

Repeat

19 – 23

5

2

Repeat

24 – 28

5

3

Repeat

29 – 33

5

4

Repeat

34 – 38

5

5

Repeat

39 – 43

5

6

Repeat

44 – 48

5

7

Repeat

49 – 53

5

8

Region

14 – 53

40

8 X 5 AA tandem repeats of G-[PAVG]-E-E-[DAYSLE]

Region

100 – 155

56

Involved in binding to CCT complex

Region

157 – 166

10

Interaction with Elongin BC complex

Natural variations

Alternative sequence

1 – 53

53

Missing in isoform 3.

VSP_007740

Alternative sequence

114 – 154

41

Missing in isoform 2.

VSP_004488

Natural variant

25

1

P → L in pheochromocytoma. dbSNP rs35460768. Ref.36 Ref.43 Ref.47

VAR_034562

Natural variant

38

1

S → P in VHLD; type II. Ref.31

VAR_005670

Natural variant

52

1

E → K in VHLD; type I. Ref.35

VAR_005671

Natural variant

63

1

L → P in pheochromocytoma. Ref.36

VAR_034987

Natural variant

64

1

R → P in pheochromocytoma. Ref.36

VAR_034988

Natural variant

65

1

S → A in pheochromocytoma. Ref.41 Ref.30 Ref.34 Ref.35

VAR_034989

Natural variant

65

1

S → L in VHLD; type I. Ref.30 Ref.34 Ref.35

VAR_005672

Natural variant

65

1

S → W in VHLD; type I. Ref.30 Ref.34 Ref.35

VAR_005673

Natural variant

66 – 73

8

Missing in VHLD; type I.

VAR_005674

Natural variant

68

1

S → W in pheochromocytoma and VHLD; type II. Ref.41 Ref.33

VAR_005675

Natural variant

70

1

E → K in VHLD; type I. Ref.35

VAR_005676

Natural variant

74

1

V → G in VHLD; type I-II. dbSNP rs5030803. Ref.30

VAR_005677

Natural variant

75

1

Missing in VHLD. Ref.1

VAR_034990

Natural variant

76

1

F → I in VHLD; type I. Ref.30 Ref.31 Ref.34

VAR_005679

Natural variant

76

1

F → L in VHLD; type I. Ref.30 Ref.31 Ref.34

VAR_005680

Natural variant

76

1

F → S in VHLD; type I. Ref.30 Ref.31 Ref.34

VAR_005681

Natural variant

76

1

Missing in VHLD; type I; common mutation. Ref.30 Ref.31 Ref.34

VAR_005678

Natural variant

78

1

N → H in VHLD; type I. Ref.30

VAR_005682

Natural variant

78

1

N → S in VHLD; type I; common mutation. dbSNP rs5030804. Ref.30

VAR_005683

Natural variant

78

1

N → T in VHLD; type I. Ref.30

VAR_005684

Natural variant

79

1

R → P in VHLD.

VAR_005685

Natural variant

80

1

S → I in VHLD; type I. Ref.30 Ref.35

VAR_005686

Natural variant

80

1

S → N in pheochromocytoma and VHLD; type I. dbSNP rs5030805. Ref.41 Ref.30 Ref.35

VAR_005688

Natural variant

80

1

S → R in VHLD; type I. Ref.30 Ref.35

VAR_005687

Natural variant

81

1

P → S in VHLD; type I. dbSNP rs5030806. Ref.30 Ref.34

VAR_005689

Natural variant

82 – 84

3

Missing in VHLD. Ref.1 Ref.27 Ref.46

VAR_005691

Natural variant

82

1

R → P in VHLD; type I. Ref.1

VAR_005690

Natural variant

84

1

V → L in VHLD; type II and type 2C. dbSNP rs5030827. Ref.27 Ref.46

VAR_005692

Natural variant

86

1

P → A in VHLD; type I. Ref.30 Ref.34 Ref.35

VAR_005693

Natural variant

86

1

P → H in VHLD. Ref.30 Ref.34 Ref.35

VAR_008097

Natural variant

86

1

P → L in VHLD; type I. Ref.30 Ref.34 Ref.35

VAR_005694

Natural variant

86

1

P → R in VHLD; type I. Ref.30 Ref.34 Ref.35

VAR_005695

Natural variant

86

1

P → S in VHLD. Ref.30 Ref.34 Ref.35

VAR_005696

Natural variant

88

1

W → R in VHLD; type I. Ref.30 Ref.34 Ref.35

VAR_005697

Natural variant

88

1

W → S in VHLD; type I. Ref.30 Ref.34 Ref.35

VAR_005698

Natural variant

89

1

L → H in lung cancer. Ref.30

VAR_005699

Natural variant

89

1

L → P in VHLD; type I. dbSNP rs5030807. Ref.30

VAR_005700

Natural variant

91

1

F → L in cerebellar hemangioblastoma. Ref.35

VAR_005701

Natural variant

92 – 97

6

Missing in VHLD; type I.

VAR_005702

Natural variant

93

1

G → C in pheochromocytoma and VHLD; type II. dbSNP rs5030808. Ref.41 Ref.37

VAR_005703

Natural variant

93

1

G → D in VHLD. Ref.37

VAR_005704

Natural variant

93

1

G → S in pheochromocytoma and VHLD; type II. dbSNP rs5030808. Ref.41 Ref.37

VAR_005705

Natural variant

96

1

Q → P in VHLD; type I. Ref.29

VAR_005706

Natural variant

98

1

Y → H in pheochromocytoma and VHLD; type II. dbSNP rs5030809. Ref.41

VAR_005707

Natural variant

101

1

L → G in VHLD; type I; requires 2 nucleotide substitutions. Ref.30 Ref.34

VAR_005708

Natural variant

101

1

L → R in VHLD; type I. Ref.30 Ref.34

VAR_005709

Natural variant

104

1

G → A in cerebellar hemangioblastoma. Ref.35

VAR_005710

Natural variant

105

1

T → P in VHLD; type I. Ref.35

VAR_005711

Natural variant

106

1

G → D in lung cancer.

VAR_005712

Natural variant

107

1

R → G in pheochromocytoma. Ref.41 Ref.34

VAR_034991

Natural variant

107

1

R → P in VHLD; type I. Ref.34

VAR_005713

Natural variant

110

1

H → Y: dbSNP rs17855706. Ref.5

VAR_055087

Natural variant

111

1

S → C in VHLD; type II. Ref.30 Ref.34

VAR_005714

Natural variant

111

1

S → N in VHLD; type I. Ref.30 Ref.34

VAR_005715

Natural variant

111

1

S → R in VHLD; type I. Ref.30 Ref.34

VAR_005716

Natural variant

112

1

Y → H in VHLD; type IIA. Ref.38

VAR_005717

Natural variant

112

1

Y → N in VHLD. Ref.38

VAR_034992

Natural variant

114

1

G → C in VHLD; type II. Ref.28 Ref.30

VAR_005718

Natural variant

114

1

G → R in VHLD; type I-II. Ref.28 Ref.30

VAR_005719

Natural variant

114

1

G → S in VHLD; type II. Ref.28 Ref.30

VAR_005720

Natural variant

115

1

H → Q in VHLD; type II. Ref.30 Ref.35

VAR_005723

Natural variant

115

1

H → R in VHLD; type II. Ref.30 Ref.35

VAR_008098

Natural variant

115

1

H → Y in VHLD; type I. dbSNP rs5030811. Ref.30 Ref.35

VAR_005722

Natural variant

116

1

L → V in VHLD. Ref.29

VAR_005724

Natural variant

117

1

W → C in VHLD; type I. Ref.30 Ref.34 Ref.35

VAR_005725

Natural variant

118

1

L → P in VHLD; type I. dbSNP rs5030830. Ref.29 Ref.30 Ref.35

VAR_005726

Natural variant

118

1

L → R in VHLD. Ref.29 Ref.30 Ref.35

VAR_005727

Natural variant

119

1

F → L in pheochromocytoma and VHLD; type II. Ref.41 Ref.28

VAR_005728

Natural variant

119

1

F → S in VHLD; type II. Ref.28

VAR_005729

Natural variant

121

1

D → G in VHLD; type I. dbSNP rs5030832. Ref.30

VAR_005730

Natural variant

122

1

A → I in pheochromocytoma; requires 2 nucleotide substitutions. Ref.41

VAR_034993

Natural variant

126

1

D → Y in ECYT2. Ref.45

VAR_034994

Natural variant

128

1

L → F in VHLD; type II.

VAR_005731

Natural variant

129

1

L → LE in VHLD.

VAR_005732

Natural variant

130

1

V → L in ECYT2 and VHLD; type I.

VAR_005733

Natural variant

131

1

N → K in VHLD; type I. Ref.34 Ref.35

VAR_005734

Natural variant

131

1

N → T in VHLD; type I. Ref.34 Ref.35

VAR_005735

Natural variant

135

1

L → F in hemangioblastoma. Ref.22

VAR_034995

Natural variant

136

1

F → C in pheochromocytoma and VHLD; type II. Ref.41 Ref.35

VAR_005737

Natural variant

136

1

F → S in VHLD. Ref.35

VAR_005736

Natural variant

136

1

F → Y in VHLD. Ref.35

VAR_008099

Natural variant

143

1

D → E in VHLD; type II. Ref.28

VAR_005738

Natural variant

145

1

Q → H in VHLD.

VAR_008100

Natural variant

147

1

I → T in pheochromocytoma. Ref.36

VAR_034996

Natural variant

148

1

Missing in VHLD; type I.

VAR_005739

Natural variant

149

1

A → T in VHLD; type II. Ref.32

VAR_005740

Natural variant

154

1

P → L in VHLD; type II.

VAR_005741

Natural variant

155

1

V → G in VHLD; type II. Ref.37

VAR_005742

Natural variant

155

1

V → M in VHLD; with RCC. Ref.37

VAR_008101

Natural variant

156

1

Y → C in pheochromocytoma and VHLD; type I. Ref.41 Ref.43 Ref.35

VAR_005743

Natural variant

156

1

Y → D in VHLD; type I. Ref.35

VAR_005744

Natural variant

156

1

Y → N in pheochromocytoma. Ref.41 Ref.43 Ref.35

VAR_034997

Natural variant

157

1

T → I in VHLD; type II. Ref.35 Ref.37

VAR_005746

Natural variant

157

1

T → TF in VHLD; type I. Ref.35 Ref.37

VAR_005747

Natural variant

158

1

L → P in VHLD; type I-II; abolishes release from chaperonin complex and the interaction with Elongin BC complex. Ref.12 Ref.30 Ref.35

VAR_005748

Natural variant

158

1

L → V in VHLD; type I. Ref.12 Ref.30 Ref.35

VAR_005749

Natural variant

159

1

K → E in VHLD; type II.

VAR_005750

Natural variant

161

1

R → G in VHLD; type II. Ref.30 Ref.35

VAR_005753

Natural variant

161

1

R → P in pheochromocytoma and VHLD; type I. Ref.41 Ref.30 Ref.35

VAR_005752

Natural variant

161

1

R → Q in pheochromocytoma and VHLD; type II. Ref.41 Ref.30 Ref.35

VAR_005751

Natural variant

162

1

C → F in VHLD; type I; No effect on interaction with HIF1A nor on HIF1A degradation. Ref.30 Ref.31 Ref.34 Ref.35

VAR_005754

Natural variant

162

1

C → R in VHLD; type I. Ref.30 Ref.31 Ref.34 Ref.35

VAR_005755

Natural variant

162

1

C → W in VHLD; type I-II. dbSNP rs5030622. Ref.30 Ref.31 Ref.34 Ref.35

VAR_005756

Natural variant

162

1

C → Y in VHLD; type I. Ref.30 Ref.31 Ref.34 Ref.35

VAR_005757

Natural variant

163

1

L → P in RCC1; with paraneoplastic erythrocytosis; inhibits binding to HIF1AN. Ref.40

VAR_034998

Natural variant

164

1

Q → H in VHLD. Ref.28 Ref.30

VAR_008102

Natural variant

164

1

Q → R in VHLD; type II. Ref.28 Ref.30

VAR_005758

Natural variant

166

1

V → D in VHLD; with RCC. Ref.29 Ref.35

VAR_008103

Natural variant

166

1

V → F in VHLD; type IIA. Ref.29 Ref.35

VAR_005759

Natural variant

167

1

R → G in VHLD; type I-II. Ref.27 Ref.30 Ref.34 Ref.35

VAR_005760

Natural variant

167

1

R → Q in pheochromocytoma and VHLD; type II; common mutation. dbSNP rs5030821. Ref.41 Ref.27 Ref.30 Ref.34 Ref.35

VAR_005761

Natural variant

167

1

R → W in pheochromocytoma and VHLD; type II; common mutation. dbSNP rs5030820. Ref.41 Ref.27 Ref.30 Ref.34 Ref.35

VAR_005762

Natural variant

170

1

V → D in VHLD; type II. Ref.29 Ref.30 Ref.35

VAR_005763

Natural variant

170

1

V → F in VHLD; type II. Ref.29 Ref.30 Ref.35

VAR_005764

Natural variant

170

1

V → G in VHLD; type I. Ref.29 Ref.30 Ref.35

VAR_005765

Natural variant

175

1

Y → D in VHLD; type I. Ref.34

VAR_005766

Natural variant

176

1

R → W in VHLD.

VAR_008104

Natural variant

177

1

R → RLRVKPE in VHLD; type I.

VAR_005767

Natural variant

178

1

L → P in VHLD; type I-II; common mutation. Ref.30

VAR_005768

Natural variant

178

1

L → Q in VHLD; type II. dbSNP rs5030822. Ref.30

VAR_005769

Natural variant

180

1

I → V in VHLD; type I. Ref.30

VAR_005770

Natural variant

184

1

L → P in VHLD; type I. Ref.30 Ref.34

VAR_005772

Natural variant

184

1

L → R in VHLD; type I. Ref.30 Ref.34

VAR_005771

Natural variant

186

1

E → K in VHLD; type I. Ref.29 Ref.30 Ref.34

VAR_005773

Natural variant

186

1

Missing in VHLD. Ref.29 Ref.30 Ref.34

VAR_005774

Natural variant

188

1

L → P in VHLD; type I-II. Ref.30 Ref.35

VAR_005775

Natural variant

188

1

L → Q in VHLD; type I. Ref.30 Ref.35

VAR_005776

Natural variant

188

1

L → V in ECYT2, pheochromocytoma and VHLD; type IIA. dbSNP rs5030824.

VAR_005777

Natural variant

191

1

H → D in ECYT2. dbSNP rs28940301. Ref.42

VAR_034999

Natural variant

192

1

P → S in ECYT2. dbSNP rs28940300. Ref.42

VAR_035000

Natural variant

198

1

L → Q in pheochromocytoma. Ref.41

VAR_035001

Natural variant

198

1

L → R in ECY2 and VHLD; type II.

VAR_005778

Natural variant

200

1

R → W in ECYT2 and VHLD; type I. dbSNP rs28940298.

VAR_005779

Experimental info

Mutagenesis

98

1

Y → N: No interaction with HIF1A. No HIF1A degradation. Ref.13

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

213

Helix Strand Turn

Details...

Beta strand

71 – 78

8

Beta strand

80 – 82

3

Beta strand

84 – 89

6

Beta strand

95 – 97

3

Beta strand

105 – 112

8

Beta strand

116 – 121

6

Turn

122 – 124

3

Beta strand

147 – 152

6

Helix

158 – 169

12

Helix

172 – 177

6

Helix

182 – 189

8

Helix

194 – 206

13

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (VHL30) (VHLp24(MPR)) [UniParc]. Last modified December 15, 1998. Version 2. Checksum: BA5D6765FBC16EA7	FASTA	213	24,153
	10 20 30 40 50 60 MPRRAENWDE AEVGAEEAGV EEYGPEEDGG EESGAEESGP EESGPEELGA EEEMEAGRPR 70 80 90 100 110 120 PVLRSVNSRE PSQVIFCNRS PRVVLPVWLN FDGEPQPYPT LPPGTGRRIH SYRGHLWLFR 130 140 150 160 170 180 DAGTHDGLLV NQTELFVPSL NVDGQPIFAN ITLPVYTLKE RCLQVVRSLV KPENYRRLDI 190 200 210 VRSLYEDLED HPNVQKDLER LTQERIAHQR MGD
	Isoform 2. Checksum: 46E2C22E8C98393D	FASTA	172	19,654
	10 20 30 40 50 60 MPRRAENWDE AEVGAEEAGV EEYGPEEDGG EESGAEESGP EESGPEELGA EEEMEAGRPR 70 80 90 100 110 120 PVLRSVNSRE PSQVIFCNRS PRVVLPVWLN FDGEPQPYPT LPPGTGRRIH SYRVYTLKER 130 140 150 160 170 CLQVVRSLVK PENYRRLDIV RSLYEDLEDH PNVQKDLERL TQERIAHQRM GD
	Isoform 3 (VHL19) (VHLp18(MEA)). Checksum: 2644C3B8C3A87D64	FASTA	160	18,532
	10 20 30 40 50 60 MEAGRPRPVL RSVNSREPSQ VIFCNRSPRV VLPVWLNFDG EPQPYPTLPP GTGRRIHSYR 70 80 90 100 110 120 GHLWLFRDAG THDGLLVNQT ELFVPSLNVD GQPIFANITL PVYTLKERCL QVVRSLVKPE 130 140 150 160 NYRRLDIVRS LYEDLEDHPN VQKDLERLTQ ERIAHQRMGD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of the von Hippel-Lindau disease tumor suppressor gene." Latif F., Tory K., Gnarra J., Yao M., Duh F.-M., Orcutt M.L., Stackhouse T., Kuzmin I., Modi W., Geil L., Schmidt L., Zhou F., Li H., Wei M.H., Chen F., Glenn G., Choyke P., Walther M.M. , Weng Y., Duan D.-S.R., Dean M., Glavac D., Richards F.M., Crossey P.A., Ferguson-Smith M.A., le Paslier D., Chumakov I., Cohen D., Chinault A.C., Maher E.R., Linehan W.M., Zbar B., Lerman M.I. Science 260:1317-1320(1993) [PubMed: 8493574] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), VARIANTS VHLD ILE-75 DEL AND ARG-82--84-VAL DEL, ALTERNATIVE SPLICING (ISOFORM 2).
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[3]	"The DNA sequence, annotation and analysis of human chromosome 3." Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J. , Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A. Nature 440:1194-1198(2006) [PubMed: 16641997] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), VARIANT TYR-110.
[6]	Wenzel M. Submitted (APR-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 33-67 AND 156-213, VARIANT PRO-163. Tissue: Renal cell carcinoma.
[7]	"Expression of the von Hippel-Lindau disease tumour suppressor gene during human embryogenesis." Richards F.M., Schofield P.N., Fleming S., Maher E.R. Hum. Mol. Genet. 5:639-644(1996) [PubMed: 8733131] [Abstract] Cited for: EXPRESSION, ALTERNATIVE SPLICING (ISOFORMS 1 AND 2).
[8]	"The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins." Pause A., Lee S., Worrel R., Chen D.Y.T., Burgess W.H., Linehan W.M., Klausner R.D. Proc. Natl. Acad. Sci. U.S.A. 94:2156-2161(1997) [PubMed: 9122164] [Abstract] Cited for: INTERACTION WITH CUL2.
[9]	"A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor." Schoenfeld A., Davidowitz E.J., Burk R.D. Proc. Natl. Acad. Sci. U.S.A. 95:8817-8822(1998) [PubMed: 9671762] [Abstract] Cited for: ALTERNATIVE SPLICING (ISOFORM 3).
[10]	"Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C." Kibel A., Iliopoulos O., DeCaprio J.A., Kaelin W.G. Jr. Science 269:1444-1446(1995) [PubMed: 7660130] [Abstract] Cited for: INTERACTION WITH ELONGIN BC COMPLEX.
[11]	"pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation." Iliopoulos O., Ohh M., Kaelin W.G. Jr. Proc. Natl. Acad. Sci. U.S.A. 95:11661-11666(1998) [PubMed: 9751722] [Abstract] Cited for: FUNCTION OF ISOFORM 3, SUBCELLULAR LOCATION.
[12]	"Formation of the VHL-elongin BC tumor suppressor complex is mediated by the chaperonin TRiC." Feldman D.E., Thulasiraman V., Ferreyra R.G., Frydman J. Mol. Cell 4:1051-1061(1999) [PubMed: 10635329] [Abstract] Cited for: INTERACTION WITH CHAPERONES, VARIANT VHLD PRO-158.
[13]	"Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein." Tanimoto K., Makino Y., Pereira T., Poellinger L. EMBO J. 19:4298-4309(2000) [PubMed: 10944113] [Abstract] Cited for: INTERACTION WITH HIF1A, FUNCTION, CHARACTERIZATION OF VARIANT PHE-162, MUTAGENESIS OF TYR-98.
[14]	"Muf1, a novel elongin BC-interacting leucine-rich repeat protein that can assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase." Kamura T., Burian D., Yan Q., Schmidt S.L., Lane W.S., Querido E., Branton P.E., Shilatifard A., Conaway R.C., Conaway J.W. J. Biol. Chem. 276:29748-29753(2001) [PubMed: 11384984] [Abstract] Cited for: IDENTIFICATION IN E3 UBIQUITIN LIGASE COMPLEXES.
[15]	"FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity." Mahon P.C., Hirota K., Semenza G.L. Genes Dev. 15:2675-2686(2001) [PubMed: 11641274] [Abstract] Cited for: INTERACTION WITH HIF1AN; HIF1A AND HISTONE DEACETYLASES. Tissue: Brain.
[16]	"Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel-Lindau tumor suppressor protein." Li Z., Na X., Wang D., Schoen S.R., Messing E.M., Wu G. J. Biol. Chem. 277:4656-4662(2002) [PubMed: 11739384] [Abstract] Cited for: INTERACTION WITH UBP33.
[17]	"The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1." Zhou M.I., Wang H., Ross J.J., Kuzmin I., Xu C., Cohen H.T. J. Biol. Chem. 277:39887-39898(2002) [PubMed: 12169691] [Abstract] Cited for: INTERACTION WITH PHF17.
[18]	"The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway." Gemmill R.M., Bemis L.T., Lee J.P., Sozen M.A., Baron A., Zeng C., Erickson P.F., Hooper J.E., Drabkin H.A. Oncogene 21:3507-3516(2002) [PubMed: 12032852] [Abstract] Cited for: INTERACTION WITH RNF139.
[19]	"Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in signaling." Min J.-H., Yang H., Ivan M., Gertler F., Kaelin W.G. Jr., Pavletich N.P. Science 296:1886-1889(2002) [PubMed: 12004076] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 54-213 IN COMPLEX WITH 556-575 OF HIF1A; TCEB1 AND TCEB2.
[20]	"Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL." Hon W.-C., Wilson M.I., Harlos K., Claridge T.D.W., Schofield C.J., Pugh C.W., Maxwell P.H., Ratcliffe P.J., Stuart D.I., Jones E.Y. Nature 417:975-978(2002) [PubMed: 12050673] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 52-213 IN COMPLEX WITH 549-582 OF HIF1A; 17-112 OF TCEB1 AND TCEB2.
[21]	"Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function." Stebbins C.E., Kaelin W.G. Jr., Pavletich N.P. Science 284:455-461(1999) [PubMed: 10205047] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 54-213 IN COMPLEX WITH 17-112 OF TCEB1 AND TCEB2.
[22]	"Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas." Kanno H., Kondo K., Ito S., Yamamoto I., Fujii S., Torigoe S., Sakai N., Hosaka M., Shuin T., Yao M. Cancer Res. 54:4845-4847(1994) [PubMed: 8069849] [Abstract] Cited for: VARIANT HEMANGIOBLASTOMA PHE-135.
[23]	"Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer cell lines." Sekido Y., Bader S., Latif F., Gnarra J.R., Gazdar A.F., Linehan W.M., Zbar B., Lerman M.I., Minna J.D. Oncogene 9:1599-1604(1994) [PubMed: 8183553] [Abstract] Cited for: VARIANTS IN LUNG CANCER.
[24]	"Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype." Crossey P.A., Richards F.M., Foster K., Green J.S., Prowse A., Latif F., Lerman M.I., Zbar B., Affara N.A., Ferguson-Smith M.A., Maher E.R. Hum. Mol. Genet. 3:1303-1308(1994) [PubMed: 7987306] [Abstract] Cited for: VARIANTS VHLD.
[25]	"Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype." Chen F., Kishida T., Yao M., Hustad T., Glavac D., Dean M., Gnarra J.R., Orcutt M.L., Duh F.-M., Glenn G., Green J.S., Hsia Y.E., Lamiell J., Li H., Wei M.H., Schmidt L., Tory K., Kuzmin I. , Stackhouse T., Latif F., Linehan W.M., Lerman M.I., Zbar B. Hum. Mutat. 5:66-75(1995) [PubMed: 7728151] [Abstract] Cited for: VARIANTS VHLD.
[26]	"Germline mutations in the von Hippel-Lindau disease (VHL) gene in Japanese VHL. Clinical Research Group for VHL in Japan." Kondo K., Sakai N., Kaneko S., Kobayashi K., Hosaka M., Ito S., Fujii S., Yamamoto I., Kim I., Miyagami M., Shidara N., Shinohara N., Koyanagi T., Kato N., Yamanaka H., Kuratu J., Fujioka M., Nakatsu H. , Shimazaki J., Yoshida J., Sugita K., Hirao Y., Okajima E., Tanigawa T., Sato S., Fujino H., Nagata M., Kanayama H., Kagawa S., Yamashima T., Furuta T., Saito Y., Kanno H., Yao M., Shuin T. Hum. Mol. Genet. 4:2233-2237(1995) [PubMed: 8634692] [Abstract] Cited for: VARIANTS VHLD.
[27]	"Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma." Crossey P.A., Eng C., Ginalska-Malinowska M., Lennard T.W.J., Wheeler D.C., Ponder B.A.J., Maher E.R. J. Med. Genet. 32:885-886(1995) [PubMed: 8592333] [Abstract] Cited for: VARIANTS VHLD LEU-84 AND TRP-167.
[28]	"Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas." Eng C., Crossey P.A., Mulligan L.M., Healey C.S., Houghton C., Prowse A., Chew S.L., Dahia P.L.M., O'Riordan J.L.H., Toledo S.P.A., Smith D.P., Maher E.R., Ponder B.A.J. J. Med. Genet. 32:934-937(1995) [PubMed: 8825918] [Abstract] Cited for: VARIANTS VHLD SER-114; SER-119; GLU-143 AND ARG-164.
[29]	"Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations." Maher E.R., Webster A.R., Richards F.M., Green J.S., Crossey P.A., Payne S.J., Moore A.T. J. Med. Genet. 33:328-332(1996) [PubMed: 8730290] [Abstract] Cited for: VARIANTS VHLD PRO-96; VAL-116; ARG-118; PHE-166; ASP-170 AND GLU-186 DEL.
[30]	"Germline mutations in the von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan." Zbar B., Kishida T., Chen F., Schmidt L., Maher E.R., Richards F.M., Crossey P.A., Webster A.R., Affara N.A., Ferguson-Smith M.A., Brauch H., Glavac D., Neumann H.P.H., Tisherman S., Mulvihill J.J., Gross D.J., Shuin T., Whaley J. , Seizinger B., Kley N., Olschwang S., Boisson C., Richard S., Lips C.H.M., Linehan W.M., Lerman M.I. Hum. Mutat. 8:348-357(1996) [PubMed: 8956040] [Abstract] Cited for: VARIANTS VHLD LEU-65; TRP-65; GLY-74; PHE-76 DEL; ILE-76; HIS-78; SER-78; THR-78; ARG-80; ASN-80; ILE-80; SER-81; ALA-86; LEU-86; ARG-88; SER-88; PRO-89; ARG-101; ARG-111; ASN-111; CYS-114; TYR-115; CYS-117; PRO-118; GLY-121; LEU-130; PRO-158; VAL-158; PRO-161; ARG-162; PHE-162; TYR-162; TRP-162; ARG-164; GLN-167; TRP-167; GLY-170; PRO-178; VAL-180; ARG-184; PRO-184; LYS-186; GLN-188 AND TRP-200.
[31]	"Germline mutations detected in the von Hippel-Lindau disease tumor suppressor gene by Southern blot and direct genomic DNA sequencing." Li C., Weber G., Ekman P., Lagercrantz J., Norlen B.J., Aakerstroem G., Nordenskjoeld M., Bergerheim U.S.R. Hum. Mutat. Suppl. 1:S31-S33(1998) [PubMed: 9452032] [Abstract] Cited for: VARIANTS VHLD PRO-38; LEU-76 AND PHE-162.
[32]	"Three novel mutations in the von Hippel-Lindau tumour suppressor gene in Italian patients." Mandich P., Montera M., Bellone E., Trojani A., Daniele S., Ajmar F. Hum. Mutat. Suppl. 1:S268-S270(1998) [PubMed: 9452106] [Abstract] Cited for: VARIANT VHLD THR-149.
[33]	"Variable penetrance of familial pheochromocytoma associated with the von Hippel-Lindau gene mutation, S68W." Martin R., Hockey A., Walpole I., Goldblatt J. Hum. Mutat. 12:71-71(1998) [PubMed: 10627136] [Abstract] Cited for: VARIANT VHLD TRP-68.
[34]	"Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene." Stolle C., Glenn G., Zbar B., Humphrey J.S., Choyke P., Walther M., Pack S., Hurley K., Andrey C., Klausner R., Linehan W.M. Hum. Mutat. 12:417-423(1998) [PubMed: 9829911] [Abstract] Cited for: VARIANTS VHLD TRP-65; SER-76; SER-81; ARG-86; ARG-88; GLY-101; PRO-107; ASN-111; CYS-117; THR-131; PHE-162; GLY-167; ASP-175; PRO-184 AND LYS-186.
[35]	"Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma." Olschwang S., Richard S., Boisson C., Giraud S., Laurent-Puig P., Resche F., Thomas G. Hum. Mutat. 12:424-430(1998) [PubMed: 9829912] [Abstract] Cited for: VARIANTS VHLD LYS-52; LEU-65; LYS-70; ASN-80; ARG-80; SER-86; SER-88; LEU-91; ALA-104; PRO-105; GLN-115; CYS-117; PRO-118; LEU-130; LYS-131; SER-136; ASP-156; CYS-156; ILE-157; PRO-158; GLN-161; TRP-162; PHE-166; GLN-167; TRP-167; GLY-170; PRO-188 AND TRP-200.
[36]	"Germline mutations in the vhl gene in patients presenting with phaeochromocytomas." van der Harst E., de Krijger R.R., Dinjens W.N.M., Weeks L.E., Bonjer H.J., Bruining H.A., Lamberts S.W.J., Koper J.W. Int. J. Cancer 77:337-340(1998) [PubMed: 9663592] [Abstract] Cited for: VARIANTS PHEOCHROMOCYTOMA LEU-25; PRO-63; PRO-64 AND THR-147.
[37]	Murigia M. Unpublished observations (MAY-1999) Cited for: VARIANTS VHLD CYS-93; GLY-155 AND ILE-157.
[38]	"Two distinct phenotypes caused by two different missense mutations in the same codon of the VHL gene." Bradley J.F., Collins D.L., Schimke R.N., Parrott H.N., Rothberg P.G. Am. J. Med. Genet. 87:163-167(1999) [PubMed: 10533030] [Abstract] Cited for: VARIANT VHLD ASN-112.
[39]	"Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC." Gallou C., Joly D., Mejean A., Staroz F., Martin N., Tarlet G., Orfanelli M.T., Bouvier R., Droz D., Chretien Y., Marechal J.M., Richard S., Junien C., Beroud C. Hum. Mutat. 13:464-475(1999) [PubMed: 10408776] [Abstract] Cited for: VARIANTS VHLD.
[40]	"Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma." Wiesener M.S., Seyfarth M., Warnecke C., Juergensen J.S., Rosenberger C., Morgan N.V., Maher E.R., Frei U., Eckardt K.-U. Blood 99:3562-3565(2002) [PubMed: 11986208] [Abstract] Cited for: VARIANT RCC1 PRO-163, CHARACTERIZATION OF VARIANT RCC1 PRO-163.
[41]	"Germ-line mutations in nonsyndromic pheochromocytoma." The Freiburg-Warsaw-Columbus pheochromocytoma study group Neumann H.P.H., Bausch B., McWhinney S.R., Bender B.U., Gimm O., Franke G., Schipper J., Klisch J., Altehoefer C., Zerres K., Januszewicz A., Smith W.M., Munk R., Manz T., Glaesker S., Apel T.W., Treier M., Reineke M. , Walz M.K., Hoang-Vu C., Brauckhoff M., Klein-Franke A., Klose P., Schmidt H., Maier-Woelfle M., Peczkowska M., Szmigielski C., Eng C. N. Engl. J. Med. 346:1459-1466(2002) [PubMed: 12000816] [Abstract] Cited for: VARIANTS PHEOCHROMOCYTOMA ALA-65; TRP-68; ASN-80; SER-93; CYS-93; HIS-98; GLY-107; LEU-119; ILE-122; CYS-136; ASN-156; CYS-156; GLN-161; PRO-161; TRP-167; GLN-167; VAL-188 AND GLN-198.
[42]	"Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia." Pastore Y.D., Jedlickova K., Guan Y., Liu E., Fahner J., Hasle H., Prchal J.F., Prchal J.T. Am. J. Hum. Genet. 73:412-419(2003) [PubMed: 12844285] [Abstract] Cited for: VARIANTS ECYT2 VAL-188; ASP-191; SER-192 AND TRP-200.
[43]	"Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas." Gimenez-Roqueplo A.-P., Favier J., Rustin P., Rieubland C., Crespin M., Nau V., Khau Van Kien P., Corvol P., Plouin P.-F., Jeunemaitre X. Cancer Res. 63:5615-5621(2003) [PubMed: 14500403] [Abstract] Cited for: VARIANTS PHEOCHROMOCYTOMA LEU-25 AND CYS-156.
[44]	Erratum Pastore Y.D., Jedlickova K., Guan Y., Liu E., Fahner J., Hasle H., Prchal J.F., Prchal J.T. Am. J. Hum. Genet. 74:598-598(2004)
[45]	"Mutations in the VHL gene in sporadic apparently congenital polycythemia." Pastore Y.D., Jelinek J., Ang S., Guan Y., Liu E., Jedlickova K., Krishnamurti L., Prchal J.T. Blood 101:1591-1595(2003) [PubMed: 12393546] [Abstract] Cited for: VARIANTS ECYT2 TYR-126; LEU-130 AND TRP-200.
[46]	"The von Hippel-Lindau (VHL) germline mutation V84L manifests as early-onset bilateral pheochromocytoma." Abbott M.-A., Nathanson K.L., Nightingale S., Maher E.R., Greenstein R.M. Am. J. Med. Genet. A 140:685-690(2006) [PubMed: 16502427] [Abstract] Cited for: VARIANT VHLD LEU-84.
[47]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] LEU-25 AND SER-86.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneReviews

Cross-references

Sequence databases

EMBLGenBankDDBJ

AF010238 Genomic DNA. Translation: AAB64200.1.
L15409 mRNA. No translation available.
AK315799 mRNA. Translation: BAG38142.1.
AC034193 Genomic DNA. No translation available.
CH471055 Genomic DNA. Translation: EAW64064.1.
BC058831 mRNA. Translation: AAH58831.1.
U54612 Genomic DNA. Translation: AAA98614.1.
X96489 Genomic DNA. Translation: CAA65343.1.

IPI

IPI00027969.
IPI00221186.
IPI00336024.

PIR

I38926.

RefSeq

NP_000542.1.
NP_937799.1.

UniGene

Hs.517792

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1LM8	X-ray	1.85	V	54-213	[»]
1LQB	X-ray	2.00	C	54-213	[»]
1VCB	X-ray	2.70	C/F/I/L	54-213	[»]

DisProt

DP00287.

ModBase

Search...

Protein-protein interaction databases

IntAct

P40337. 235 interactions.

PTM databases

PhosphoSite

P40337.

Genome annotation databases

Ensembl

ENSG00000134086. Homo sapiens. [Contig view]

GeneID

7428.

KEGG

hsa:7428.

Organism-specific databases

GeneCards

GC03P010158.

H-InvDB

HIX0030712.

HGNC

HGNC:12687. VHL.

MIM

144700. phenotype.
171300. phenotype.
193300. phenotype.
263400. phenotype.
608537. gene.

Orphanet

717. Pheochromocytoma and secreting paraganglioma.
90042. Polycythemia, familial, primary.
151. Renal cell carcinoma, familial.
892. Von Hippel-Lindau disease.

PharmGKB

PA37307.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P40337.

HOVERGEN

P40337.

OMA

P40337. ENQRMGD.

Enzyme and pathway databases

Pathway_Interaction_DB

hif1apathway. Hypoxic and oxygen homeostasis regulation of HIF-1-alpha.
vegfr1_2_pathway. Signaling events mediated by VEGFR1 and VEGFR2.

Gene expression databases

ArrayExpress

P40337.

Bgee

P40337.

CleanEx

HS_VHL.

GermOnline

ENSG00000134086. Homo sapiens.

Family and domain databases

InterPro

IPR002714. Tumour_suppress_VHL-disease.
[Graphical view]

PANTHER

PTHR15160. VHL. 1 hit.

Pfam

PF01847. VHL. 1 hit.
[Graphical view]

ProDom

PD035809. VHL. 1 hit.
[Graphical view] [Entries sharing at least one domain]

ProtoNet

Search...

Other Resources

NextBio

29090.

SOURCE

Search...

Entry information

Entry name

VHL_HUMAN

Accession

Primary (citable) accession number: P40337
Secondary accession number(s): B2RE45, Q13599, Q6PDA9

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	December 15, 1998
Last modified:	June 16, 2009
This is version 111 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)