Phenotypes associated with this allele

• Allele Symbol: Vhl^tm1Jae
• Allele Name: targeted mutation 1, Rudolf Jaenisch
• Allele ID: MGI:2136645
• Summary: 24 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Vhl^tm1Jae/Vhl^tm1Jae	involves: 129S4/SvJae	MGI:4459904
hm2	Vhl^tm1Jae/Vhl^tm1Jae	involves: 129S4/SvJae * BALB/c	MGI:2176967
cn3	Hif1a^tm3Rsjo/Hif1a^tm3Rsjo Hprt1^tm1(Pck1-cre)Vhh/Y Vhl^tm1Jae/Vhl^tm1Jae	involves: 129 * BALB/c * C57BL/6	MGI:3621461
cn4	Arnt^tm1Bra/Arnt^tm1Bra Hprt1^tm1(Pck1-cre)Vhh/Y Vhl^tm1Jae/Vhl^tm1Jae	involves: 129 * BALB/c * C57BL/6	MGI:3621462
cn5	Hif1a^tm3Rsjo/Hif1a^tm3Rsjo Vhl^tm1Jae/Vhl^tm1Jae Speer6-ps1^Tg(Alb-cre)21Mgn/Speer6-ps1^+	involves: 129 * BALB/c * C57BL/6 * DBA	MGI:3621471
cn6	Arnt^tm1Bra/Arnt^tm1Bra Vhl^tm1Jae/Vhl^tm1Jae Speer6-ps1^Tg(Alb-cre)21Mgn/Speer6-ps1^+	involves: 129 * BALB/c * C57BL/6 * DBA	MGI:3621473
cn7	Vhl^tm1Jae/Vhl^tm1Jae Lyz2^tm1(cre)Ifo/Lyz2^+	involves: 129P2/OlaHsd * 129S4/SvJae	MGI:4418464
cn8	Hprt1^tm1(Pck1-cre)Vhh/Y Vhl^tm1Jae/Vhl^tm1Jae	involves: 129P2/OlaHsd * 129S4/SvJae * BALB/c * C57BL/6	MGI:3621460
cn9	Hif1a^tm3Rsjo/Hif1a^tm3Rsjo Vhl^tm1Jae/Vhl^tm1Jae Tg(Sp7-tTA,tetO-EGFP/cre)1Amc/0	involves: 129S1/Sv * 129S4/SvJae * 129X1/SvJ * CD-1	MGI:5432006
cn10	Epas1^tm1Mcs/Epas1^tm1Mcs Hif1a^tm3Rsjo/Hif1a^tm3Rsjo Vhl^tm1Jae/Vhl^tm1Jae Tg(Sp7-tTA,tetO-EGFP/cre)1Amc/0	involves: 129S1/Sv * 129S4/SvJae * 129X1/SvJ * CD-1	MGI:5432005
cn11	Vhl^tm1Jae/Vhl^tm1Jae Tg(Pax6-cre,GFP)2Pgr/0	involves: 129S4/SvJae	MGI:5705504
cn12	Epas1^tm1Mcs/Epas1^tm1Mcs Vhl^tm1Jae/Vhl^tm1Jae Tg(Sp7-tTA,tetO-EGFP/cre)1Amc/0	involves: 129S4/SvJae * 129X1/SvJ * CD-1	MGI:5432007
cn13	Vhl^tm1Jae/Vhl^tm1Jae Speer6-ps1^Tg(Alb-cre)21Mgn/Speer6-ps1^+	involves: 129S4/SvJae * BALB/c * C57BL/6 * DBA	MGI:2176966
cn14	Vhl^tm1Jae/Vhl^tm1Jae Tg(Cdh16-cre)91Igr/0	involves: 129S4/SvJae * BALB/c * C57BL/6J * ICR	MGI:4943542
cn15	Pten^tm1Hwu/Pten^tm1Hwu Vhl^tm1Jae/Vhl^tm1Jae Tg(Cdh16-cre)91Igr/0	involves: 129S4/SvJae * BALB/c * C57BL/6J * ICR	MGI:4943534
cn16	Tg(Fabp1-cre)1Jig/0 Vhl^tm1Jae/Vhl^tm1Jae	involves: 129S4/SvJae * BALB/c * FVB/N	MGI:4418472
cn17	Vhl^tm1Jae/Vhl^tm1Jae Speer6-ps1^Tg(Alb-cre)21Mgn/Speer6-ps1^+	involves: 129S4/SvJae * C57BL/6 * DBA	MGI:3832405
cn18	Vhl^tm1Jae/Vhl^tm1Jae Tg(NPHS2-cre)295Lbh/?	involves: 129S4/SvJae * C57BL/6 * SJL	MGI:5432351
cn19	Vhl^tm1Jae/Vhl^tm1Jae Tg(KRT14-cre)1Ipc/0	involves: 129S4/SvJae * C57BL/6 * SJL	MGI:3832401
cn20	Vhl^tm1Jae/Vhl^tm1Jae Tg(Sp7-tTA,tetO-EGFP/cre)1Amc/0	involves: 129S4/SvJae * CD-1	MGI:5432002
cn21	Vhl^tm1Jae/Vhl^tm1Jae Tg(Myh6-cre)2182Mds/0	involves: 129S4/SvJae * FVB/N	MGI:5304714
cn22	Vhl^tm1Jae/Vhl^tm1Jae Tg(Cdh16-cre)91Igr/0	involves: 129S4/SvJae * ICR	MGI:4839498
cn23	Pten^tm1Hwu/Pten^tm1Hwu Vhl^tm1Jae/Vhl^tm1Jae Tg(Cdh16-cre)91Igr/0	involves: 129S4/SvJae * ICR	MGI:4839497
cx24	Hif1a^tm1Rsjo/Hif1a^tm1Rsjo Hif1an^tm1.2Rsjo/Hif1an^tm1.2Rsjo Vhl^tm1Jae/Vhl^tm1Jae	involves: 129S1/Sv * 129S4/SvJae * 129X1/SvJ	MGI:4459906

Genotype
MGI:4459904

hm1

• Allelic Composition: Vhl^tm1Jae/Vhl^tm1Jae
• Genetic Background: involves: 129S4/SvJae

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

cellular

decreased cell proliferation ( J:160941 )

• of MEFs after 48 hours of culturing in normoxia or hypoxia conditions

Genotype
MGI:2176967

hm2

• Allelic Composition: Vhl^tm1Jae/Vhl^tm1Jae
• Genetic Background: involves: 129S4/SvJae * BALB/c

normal phenotype

no abnormal phenotype detected ( J:67505 )

Genotype
MGI:3621461

cn3

• Allelic Composition: Hif1a^tm3Rsjo/Hif1a^tm3Rsjo; Hprt1^{tm1(Pck1-cre)Vhh}/Y; Vhl^tm1Jae/Vhl^tm1Jae
• Genetic Background: involves: 129 * BALB/c * C57BL/6

renal/urinary system

kidney inflammation ( J:106705 )

♂ • pockets of inflammation

abnormal kidney morphology ( J:106705 )

♂ • dilated lymphatic vessels

abnormal kidney vasculature morphology ( J:106705 )

♂ • vascular ectasia

kidney cyst ( J:106705 )

♂ • unilateral and bilateral macroscopic cysts that vary in number and size are seen in 3 of 10 mice

♂ • multiple microscopic cysts are also seen with 3 of 10 having cysts of tubular origin and 7 of 10 having cysts of glomerular origin

♂ • cysts of both tubular and glomerular origin may occur in the same mouse

liver/biliary system

hepatic steatosis ( J:97652 )

♂

increased hepatic hemangioma incidence ( J:97652 )

♂ • cavernous hepatic hemangiomas seen in mice at 2 - 6 months of age and with increased frequency in mice older than 6 months

cardiovascular system

increased vascular endothelial cell number ( J:97652 )

♂ • proliferation of endothelial cells in hepatic blood vessels

abnormal kidney vasculature morphology ( J:106705 )

♂ • vascular ectasia

abnormal vasodilation ( J:97652 )

♂ • hepatic vascular angiectasia

neoplasm

increased hepatic hemangioma incidence ( J:97652 )

♂ • cavernous hepatic hemangiomas seen in mice at 2 - 6 months of age and with increased frequency in mice older than 6 months

hematopoietic system

polycythemia ( J:97652 )

♂ • average red blood cell count is 10.77 x 10⁶ compared to 9.3 x 10⁶ in controls

♂ • develop erythrocytosis as indicated by reddening of paws and muzzle

increased hemoglobin content ( J:97652 )

♂ • hemoglobin content is 19.38 g/dl compared to 13.24 g/dl in controls

immune system

kidney inflammation ( J:106705 )

♂ • pockets of inflammation

muscle

abnormal vasodilation ( J:97652 )

♂ • hepatic vascular angiectasia

growth/size/body

kidney cyst ( J:106705 )

♂ • unilateral and bilateral macroscopic cysts that vary in number and size are seen in 3 of 10 mice

♂ • multiple microscopic cysts are also seen with 3 of 10 having cysts of tubular origin and 7 of 10 having cysts of glomerular origin

♂ • cysts of both tubular and glomerular origin may occur in the same mouse

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
von Hippel-Lindau disease		DOID:14175	OMIM:193300	J:97652 , J:106705

Genotype
MGI:3621462

cn4

• Allelic Composition: Arnt^tm1Bra/Arnt^tm1Bra; Hprt1^{tm1(Pck1-cre)Vhh}/Y; Vhl^tm1Jae/Vhl^tm1Jae
• Genetic Background: involves: 129 * BALB/c * C57BL/6

renal/urinary system

renal/urinary system phenotype ( J:106705 )

♂N • no macroscopic or microscopic renal cysts are detected

liver/biliary system

hepatic steatosis ( J:97652 )

♂ • moderate steatosis without angiectasia or endothelial cell proliferation is seen only in mutants over 9 months of age

neoplasm

neoplasm ( J:97652 )

♂N • no hepatic hemangiomas are seen

hematopoietic system

hematopoietic system phenotype ( J:97652 )

♂N • red cell count and hemoglobin levels are similar to controls

Genotype
MGI:3621471

cn5

• Allelic Composition: Hif1a^tm3Rsjo/Hif1a^tm3Rsjo; Vhl^tm1Jae/Vhl^tm1Jae; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129 * BALB/c * C57BL/6 * DBA

liver/biliary system

hepatic steatosis ( J:97652 )

• severe steatosis

cardiovascular system

increased vascular endothelial cell number ( J:97652 )

• proliferation of endothelial cells in hepatic blood vessels

abnormal vasodilation ( J:97652 )

• hepatic vascular angiectasia

muscle

abnormal vasodilation ( J:97652 )

• hepatic vascular angiectasia

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
von Hippel-Lindau disease		DOID:14175	OMIM:193300	J:97652

Genotype
MGI:3621473

cn6

• Allelic Composition: Arnt^tm1Bra/Arnt^tm1Bra; Vhl^tm1Jae/Vhl^tm1Jae; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129 * BALB/c * C57BL/6 * DBA

liver/biliary system

liver/biliary system phenotype ( J:97652 )

N • livers appear histologically normal at 4 - 6 weeks of age

Genotype
MGI:4418464

cn7

• Allelic Composition: Vhl^tm1Jae/Vhl^tm1Jae; Lyz2^tm1(cre)Ifo/Lyz2⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S4/SvJae

immune system

increased inflammatory response ( J:107682 )

• TPA-treated ears exhibit increased edema and inflammatory infiltration compared with similarly treated wild-type ears

Genotype
MGI:3621460

cn8

• Allelic Composition: Hprt1^{tm1(Pck1-cre)Vhh}/Y; Vhl^tm1Jae/Vhl^tm1Jae
• Genetic Background: involves: 129P2/OlaHsd * 129S4/SvJae * BALB/c * C57BL/6

renal/urinary system

kidney inflammation ( J:106705 )

♂ • pockets of inflammation

abnormal kidney morphology ( J:106705 )

♂ • dilated lymphatic vessels

abnormal kidney vasculature morphology ( J:106705 )

♂ • vascular ectasia

kidney cyst ( J:106705 )

♂ • unilateral and bilateral macroscopic cysts that vary in number and size are seen in 4 of 22 mice

♂ • multiple microscopic cysts are also seen with 5 of 20 having cysts of tubular origin and 7 of 20 having cysts of glomerular origin

♂ • cysts of both tubular and glomerular origin may occur in the same mouse

liver/biliary system

hepatic steatosis ( J:97652 )

♂

increased hepatic hemangioma incidence ( J:97652 )

♂ • cavernous hepatic hemangiomas seen in mice at 2 - 6 months of age and with increased frequency in mice older than 6 months

cardiovascular system

increased vascular endothelial cell number ( J:97652 )

♂ • proliferation of endothelial cells in hepatic blood vessels

abnormal kidney vasculature morphology ( J:106705 )

♂ • vascular ectasia

abnormal vasodilation ( J:97652 )

♂ • hepatic vascular angiectasia

neoplasm

increased hepatic hemangioma incidence ( J:97652 )

♂ • cavernous hepatic hemangiomas seen in mice at 2 - 6 months of age and with increased frequency in mice older than 6 months

hematopoietic system

polycythemia ( J:97652 )

♂ • average red blood cell count is 11.7 x 10⁶ compared to 9.3 x 10⁶ in controls

♂ • develop erythrocytosis as indicated by reddening of paws and muzzle

increased hemoglobin content ( J:97652 )

♂ • hemoglobin content is 20.05 g/dl compared to 13.24 g/dl in controls

immune system

kidney inflammation ( J:106705 )

♂ • pockets of inflammation

muscle

abnormal vasodilation ( J:97652 )

♂ • hepatic vascular angiectasia

growth/size/body

kidney cyst ( J:106705 )

♂ • unilateral and bilateral macroscopic cysts that vary in number and size are seen in 4 of 22 mice

♂ • multiple microscopic cysts are also seen with 5 of 20 having cysts of tubular origin and 7 of 20 having cysts of glomerular origin

♂ • cysts of both tubular and glomerular origin may occur in the same mouse

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
von Hippel-Lindau disease		DOID:14175	OMIM:193300	J:97652 , J:106705

Genotype
MGI:5432006

cn9

• Allelic Composition: Hif1a^tm3Rsjo/Hif1a^tm3Rsjo; Vhl^tm1Jae/Vhl^tm1Jae; Tg(Sp7-tTA,tetO-EGFP/cre)1Amc/0
• Genetic Background: involves: 129S1/Sv * 129S4/SvJae * 129X1/SvJ * CD-1

hematopoietic system

increased hematocrit ( J:186085 )

homeostasis/metabolism

increased circulating erythropoietin level ( J:186085 )

Genotype
MGI:5432005

cn10

• Allelic Composition: Epas1^tm1Mcs/Epas1^tm1Mcs; Hif1a^tm3Rsjo/Hif1a^tm3Rsjo; Vhl^tm1Jae/Vhl^tm1Jae; Tg(Sp7-tTA,tetO-EGFP/cre)1Amc/0
• Genetic Background: involves: 129S1/Sv * 129S4/SvJae * 129X1/SvJ * CD-1

skeleton

decreased trabecular bone volume ( J:186085 )

decreased bone trabecula number ( J:186085 )

hematopoietic system

hematopoietic system phenotype ( J:186085 )

N • mice exhibit normal frequencies of KLS cells (hematopoietic stem cells and multipotential progenitors) numbers of red blood cells and lymphocytes and hematocrit

homeostasis/metabolism

decreased circulating erythropoietin level ( J:186085 )

Genotype
MGI:5705504

cn11

• Allelic Composition: Vhl^tm1Jae/Vhl^tm1Jae; Tg(Pax6-cre,GFP)2Pgr/0
• Genetic Background: involves: 129S4/SvJae

cardiovascular system

abnormal retina vasculature morphology ( J:217533 )

• early vertical branching from primary vascular plexuses in the retina

vision/eye

abnormal retina vasculature morphology ( J:217533 )

• early vertical branching from primary vascular plexuses in the retina

Genotype
MGI:5432007

cn12

• Allelic Composition: Epas1^tm1Mcs/Epas1^tm1Mcs; Vhl^tm1Jae/Vhl^tm1Jae; Tg(Sp7-tTA,tetO-EGFP/cre)1Amc/0
• Genetic Background: involves: 129S4/SvJae * 129X1/SvJ * CD-1

hematopoietic system

hematopoietic system phenotype ( J:186085 )

N • mice exhibit normal hematocrit

homeostasis/metabolism

decreased circulating erythropoietin level ( J:186085 )

Genotype
MGI:2176966

cn13

• Allelic Composition: Vhl^tm1Jae/Vhl^tm1Jae; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129S4/SvJae * BALB/c * C57BL/6 * DBA

Vascular tumors in Vhl^tm1.1Jae/Vhl⁺ livers and vascular lesions in Vhl^tm1Jae/Vhl^tm1Jae Speer6-ps1^{Tg(Alb-cre)21Mgn}/0 mice

mortality/aging

premature death ( J:67505 )

• die between 6 and 13 weeks of age

growth/size/body

decreased body weight ( J:67505 )

• body weight is about 50% of wild-type

enlarged liver ( J:67505 )

• severe

liver/biliary system

abnormal liver morphology ( J:67505 )

• numerous blood filled vascular cavities, but no large cavernous hemangiomas, are seen

enlarged liver ( J:67505 )

• severe

hepatic steatosis ( J:67505 , J:97652 )

• accumulation of neutral fats in hepatocytes is detectable by 2 weeks of age (J:67505)

• severe steatosis (J:97652)

cardiovascular system

abnormal blood vessel morphology ( J:67505 )

• foci of increased vascularization are present in the liver

increased vascular endothelial cell number ( J:97652 )

• proliferation of endothelial cells in hepatic blood vessels

abnormal vasodilation ( J:97652 )

• hepatic vascular angiectasia

hematopoietic system

polycythemia ( J:67505 )

muscle

abnormal vasodilation ( J:97652 )

• hepatic vascular angiectasia

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
von Hippel-Lindau disease		DOID:14175	OMIM:193300	J:67505 , J:97652

Genotype
MGI:4943542

cn14

• Allelic Composition: Vhl^tm1Jae/Vhl^tm1Jae; Tg(Cdh16-cre)91Igr/0
• Genetic Background: involves: 129S4/SvJae * BALB/c * C57BL/6J * ICR

renal/urinary system

hydronephrosis ( J:137073 )

• hydronephrosis, characterized by an expansion of the renal pelvis

• however, mutants do not display histological abnormalities in the urothelium of the renal pelvis or ureter, or in the structure of the tubules in the kidney cortex or medulla

Genotype
MGI:4943534

cn15

• Allelic Composition: Pten^tm1Hwu/Pten^tm1Hwu; Vhl^tm1Jae/Vhl^tm1Jae; Tg(Cdh16-cre)91Igr/0
• Genetic Background: involves: 129S4/SvJae * BALB/c * C57BL/6J * ICR

renal/urinary system

increased kidney cell proliferation ( J:137073 )

• cysts exhibit a 3- to 6-fold increase in the number of Ki-67-positive kidney epithelial cells per mm2 of cortex

kidney cyst ( J:137073 )

• mutants develop multiple epithelial tubule cysts in the kidney cortex and medulla

• cysts develop in all mice (14 of 14) and are seen as early as 6-8 weeks of age

• cysts arise in collecting ducts and distal tubules

• most cysts are lined by a single layer of epithelial cells (simple cysts), whereas ~8% of cysts are lined by multilayered epithelial cells with occasional papillary projections (atypical cysts)

• mutants exhibit reduced frequency of primary cilia in cysts, with distal tubule cysts displaying only ~30% ciliated cells relative to 80-90% ciliated cells in wild-type

kidney cortex cyst ( J:137073 )

• mutants develop multiple epithelial tubule cysts in the kidney cortex

kidney medulla cyst ( J:137073 )

• mutants develop multiple epithelial tubule cysts in the kidney medulla

increased kidney weight ( J:137073 )

• males and females exhibit enlarged and heavier kidneys due to epithelial tubule cysts

abnormal kidney cortex morphology ( J:137073 )

• 3 of 14 mice show isolated regions of benign squamous metaplasia within the kidney cortex

abnormal kidney epithelium morphology ( J:137073 )

• kidney epithelial cells fail to maintain their primary cilia, resulting in uncontrolled proliferation and cyst formation

abnormal renal tubule epithelial cell primary cilium morphology ( J:137073 )

• mutants exhibit reduced frequency of primary cilia in cysts, with distal tubule cysts displaying only ~30% ciliated cells relative to 80-90% ciliated cells in wild-type

abnormal kidney pelvis urothelium morphology ( J:137073 )

• hyperproliferation of the urothelium in the renal pelvis is more pronounced than in single Pten mutants

hydronephrosis ( J:137073 )

cellular

abnormal renal tubule epithelial cell primary cilium morphology ( J:137073 )

• mutants exhibit reduced frequency of primary cilia in cysts, with distal tubule cysts displaying only ~30% ciliated cells relative to 80-90% ciliated cells in wild-type

increased kidney cell proliferation ( J:137073 )

• cysts exhibit a 3- to 6-fold increase in the number of Ki-67-positive kidney epithelial cells per mm2 of cortex

neoplasm

neoplasm ( J:137073 )

N • no tumors areas seen at 3-6 months of age, when mice are euthanized to avoid renal failure

growth/size/body

kidney cyst ( J:137073 )

• mutants develop multiple epithelial tubule cysts in the kidney cortex and medulla

• cysts develop in all mice (14 of 14) and are seen as early as 6-8 weeks of age

• cysts arise in collecting ducts and distal tubules

• most cysts are lined by a single layer of epithelial cells (simple cysts), whereas ~8% of cysts are lined by multilayered epithelial cells with occasional papillary projections (atypical cysts)

• mutants exhibit reduced frequency of primary cilia in cysts, with distal tubule cysts displaying only ~30% ciliated cells relative to 80-90% ciliated cells in wild-type

kidney cortex cyst ( J:137073 )

• mutants develop multiple epithelial tubule cysts in the kidney cortex

kidney medulla cyst ( J:137073 )

• mutants develop multiple epithelial tubule cysts in the kidney medulla

increased kidney weight ( J:137073 )

• males and females exhibit enlarged and heavier kidneys due to epithelial tubule cysts

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
von Hippel-Lindau disease		DOID:14175	OMIM:193300	J:137073

Genotype
MGI:4418472

cn16

• Allelic Composition: Tg(Fabp1-cre)1Jig/0; Vhl^tm1Jae/Vhl^tm1Jae
• Genetic Background: involves: 129S4/SvJae * BALB/c * FVB/N

digestive/alimentary system

abnormal digestive system physiology ( J:93476 )

• mice exposed to hypoxic conditions exhibit reduced impairment in intestinal barrier function compared with similarly treated wild-type mice

decreased susceptibility to induced colitis ( J:93476 )

• TNBS-treated mice do not exhibit weight loss, as severe reduction in colon length, as much mortality, or an increase in intestinal permeability unlike similarly treated wild-type mice

immune system

decreased susceptibility to induced colitis ( J:93476 )

• TNBS-treated mice do not exhibit weight loss, as severe reduction in colon length, as much mortality, or an increase in intestinal permeability unlike similarly treated wild-type mice

Genotype
MGI:3832405

cn17

• Allelic Composition: Vhl^tm1Jae/Vhl^tm1Jae; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * DBA

mortality/aging

premature death ( J:144666 )

• mice die at 6 to 8 weeks of age

liver/biliary system

increased hepatocyte proliferation ( J:144666 )

abnormal liver morphology ( J:144666 )

• at 6 weeks, the liver is friable and stippled with irregular yellow spots on a reddish black background unlike in wild-type mice

• hepatic vascularity is increased compared to in wild-type mice

increased liver weight ( J:144666 )

• at 6 weeks of age

abnormal hepatocyte morphology ( J:144666 )

• livers contain irregular, dilated, blood filled sinusoids and cytoplasmic vacuolizations within hepatocytes with eccentric nuclei unlike in wild-type mice

hepatic steatosis ( J:144666 )

• in a mixed micro- and macrovesicular steatotic pattern

hematopoietic system

increased hematocrit ( J:144666 )

reticulocytosis ( J:144666 )

cardiovascular system

abnormal blood vessel morphology ( J:144666 )

• hepatic vascularity is increased compared to in wild-type mice

growth/size/body

decreased body size ( J:144666 )

• mice are runted

increased liver weight ( J:144666 )

• at 6 weeks of age

integument

reddish skin ( J:144666 )

• of paws and unfurred skin by 4 to 6 weeks of age

cellular

increased hepatocyte proliferation ( J:144666 )

Genotype
MGI:5432351

cn18

• Allelic Composition: Vhl^tm1Jae/Vhl^tm1Jae; Tg(NPHS2-cre)295Lbh/?
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * SJL

mortality/aging

premature death ( J:162099 )

• premature death beginning at ~6 months of age in mice with the highest levels of albuminuria (>1000 ug/ml)

• however, nonproteinuric mice survive to >1 year of age without overt health problems

renal/urinary system

renal/urinary system phenotype ( J:162099 )

N • at P5, all mice exhibit normal comma and S-shaped nephric figures as well as normal capillary loop stage and maturing stage glomeruli relative to wild-type controls

N • no changes in peritubular microvessels or larger arterioles and veins are observed

dilated glomerular capillary ( J:162099 )

• dilated glomerular capillary lumen noted in mice with severe albuminuria as early as 4 weeks of age

increased mesangial cell number ( J:162099 )

• mesangial hypercellularity noted in mice with severe albuminuria at 4 weeks of age

albuminuria ( J:162099 )

• at 4 weeks of age, mice exhibit varying levels of albuminuria ranging from no detectable albumin to >1000 ug/ml in severe cases

• 54% of mice (males and females) are nonproteinuric with albumin levels ranging from 2.9 to 29.7 ug/ml, similar to those in wild-type controls

dilated kidney collecting duct ( J:162099 )

• dilated medullary collecting ducts noted in nonproteinuric mice at 4 weeks of age

podocyte foot process effacement ( J:162099 )

• podocyte foot process broadening noted in all nonproteinuric mice at 4 weeks of age

decreased podocyte number ( J:162099 )

• significant decrease in podocyte number noted in both proteinuric and nonproteinuric mice at 4 weeks of age, as shown WT1 staining

abnormal renal glomerulus basement membrane morphology ( J:162099 )

• incompletely fused or fragmented GBM noted on the subendothelial side of the capillary loop in nonproteinuric mice at 4 weeks of age

increased renal glomerulus basement membrane thickness ( J:162099 )

• abnormal GBM thickenings with numerous subepithelial "humps" and subendothelial matrix projections noted in nonproteinuric mice at 4 weeks of age

• at 16 weeks of age, overall GBM thickness in nonproteinuric mice increases to ~100 nm more than in wild-type controls

• ectopic deposition of collagen alpha1alpha2alpha1(IV) noted in GBM humps beneath podocytes

expanded mesangial matrix ( J:162099 )

• mesangial matrix expansion noted in mice with severe albuminuria at 4 weeks of age

• slightly increased mesangial matrix noted in nonproteinuric mice at 4 weeks of age

glomerular crescent ( J:162099 )

• glomerular crescents noted in mice with severe albuminuria at 4 weeks of age

renal glomerulus fibrosis ( J:162099 )

• severely fibrotic glomeruli noted in mice with massive albuminuria at 25 weeks of age

renal interstitial fibrosis ( J:162099 )

• noted in mice with severe albuminuria at 25 weeks of age

dilated renal tubule ( J:162099 )

• dilated tubules containing proteinaceous casts and cellular debris noted in mice with severe albuminuria at 25 weeks of age

• occasional dilated tubules in nonproteinuric mice at 4 weeks of age

renal cast ( J:162099 )

• proteinaceous casts detected in dilated tubules of mice with severe albuminuria at 25 weeks of age

• proteinaceous casts also noted in dilated medullary collecting ducts of nonproteinuric mice at 4 weeks of age

kidney failure ( J:162099 )

• end-stage renal failure observed in mice with the highest levels of albuminuria

homeostasis/metabolism

increased blood urea nitrogen level ( J:162099 )

• at 33-41-weeks of age, increased BUN levels are noted in association with only the highest levels of albuminuria (>1000 ug/ml)

• severely nephrotic mice show a 6-fold increase in BUN levels relative to mice with lower levels of albuminuria

edema ( J:162099 )

• edema noted in mice with the highest levels of albuminuria

albuminuria ( J:162099 )

• at 4 weeks of age, mice exhibit varying levels of albuminuria ranging from no detectable albumin to >1000 ug/ml in severe cases

• 54% of mice (males and females) are nonproteinuric with albumin levels ranging from 2.9 to 29.7 ug/ml, similar to those in wild-type controls

growth/size/body

cachexia ( J:162099 )

• wasting noted in mice with the highest levels of albuminuria

cardiovascular system

dilated glomerular capillary ( J:162099 )

• dilated glomerular capillary lumen noted in mice with severe albuminuria as early as 4 weeks of age

cellular

increased mesangial cell number ( J:162099 )

• mesangial hypercellularity noted in mice with severe albuminuria at 4 weeks of age

Genotype
MGI:3832401

cn19

• Allelic Composition: Vhl^tm1Jae/Vhl^tm1Jae; Tg(KRT14-cre)1Ipc/0
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * SJL

growth/size/body

decreased body size ( J:144666 )

• at weaning mice are runted

cardiovascular system

dilated vasculature ( J:144666 )

• the number of dilated dermal blood vessels is increased compared to in wild-type mice

increased vascular permeability ( J:144666 )

• following application of an inflammatory stimuli

integument

increased keratinocyte proliferation ( J:144666 )

• keratinocyte proliferation is increased

alopecia ( J:144666 )

• partial by weaning

epidermal hyperplasia ( J:144666 )

reddish skin ( J:144666 )

• at P5

cellular

increased keratinocyte proliferation ( J:144666 )

• keratinocyte proliferation is increased

Genotype
MGI:5432002

cn20

• Allelic Composition: Vhl^tm1Jae/Vhl^tm1Jae; Tg(Sp7-tTA,tetO-EGFP/cre)1Amc/0
• Genetic Background: involves: 129S4/SvJae * CD-1

hematopoietic system

enlarged spleen ( J:186085 )

abnormal blood cell morphology/development ( J:186085 )

• 3-fold increase in the frequency of KLS cells (hematopoietic stem cells and multipotential progenitors)

extramedullary hematopoiesis ( J:186085 )

decreased bone marrow cell number ( J:186085 )

increased erythroid progenitor cell number ( J:186085 )

• 1.4-fold in the bone marrow

• 4-fold in the spleen

• increased mature erythroid (CFU-E) compared with immature erythroid (BFU-E)

increased erythrocyte cell number ( J:186085 )

polycythemia ( J:186085 )

• severe by 2 months

increased hematocrit ( J:186085 )

decreased lymphocyte cell number ( J:186085 )

increased hematopoietic stem cell number ( J:186085 )

skeleton

increased trabecular bone volume ( J:186085 )

• 2.5-fold in the metaphyseal region

increased osteoblast cell number ( J:186085 )

• increased trabecular osteoblasts

increased bone trabecula number ( J:186085 )

increased trabecular bone mass ( J:186085 )

• in the metaphyseal and diaphyseal regions

cardiovascular system

abnormal angiogenesis ( J:186085 )

• hypervasculatization of the bone

growth/size/body

decreased body size ( J:186085 )

enlarged spleen ( J:186085 )

homeostasis/metabolism

increased circulating erythropoietin level ( J:186085 )

immune system

enlarged spleen ( J:186085 )

decreased lymphocyte cell number ( J:186085 )

limbs/digits/tail

abnormal foot pad morphology ( J:186085 )

• red paw

Genotype
MGI:5304714

cn21

• Allelic Composition: Vhl^tm1Jae/Vhl^tm1Jae; Tg(Myh6-cre)2182Mds/0
• Genetic Background: involves: 129S4/SvJae * FVB/N

mortality/aging

premature death ( J:179490 )

• mean survival is 9 weeks

postnatal lethality, complete penetrance ( J:193425 )

• die between P16 and P18 due to sudden cardiac death

cardiovascular system

increased angiogenesis ( J:179490 )

increased heart weight ( J:179490 )

• at 5 weeks and severe at 8 weeks

abnormal heart left ventricle morphology ( J:179490 )

• at 8 weeks, mice exhibit reduced left ventricular wall thickness and increased left ventricular end-diastolic dimension compared with control mice

decreased heart ventricle muscle contractility ( J:179490 )

• at 5 weeks and severe at 8 weeks

decreased heart rate ( J:193425 )

• neonates exhibit decreased heart rate at 10 days after birth

irregular heartbeat ( J:193425 )

• neonates exhibit frequent cardiac arrhythmia, consistent with sudden cardiac death

prolonged QRS complex duration ( J:193425 )

• neonates exhibit increased QRS at 10 days after birth

prolonged QT interval ( J:193425 )

• exhibit increased QTc (c denotes correction for heart rate) and QTc dispersion at 10 days after birth

cardiomyopathy ( J:179490 )

• severe at 8 weeks of age

muscle

decreased heart ventricle muscle contractility ( J:179490 )

• at 5 weeks and severe at 8 weeks

cardiomyopathy ( J:179490 )

• severe at 8 weeks of age

cellular

decreased mitochondrial number ( J:179490 )

• myocytes exhibit mitochondrial loss

growth/size/body

increased heart weight ( J:179490 )

• at 5 weeks and severe at 8 weeks

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
sudden infant death syndrome		DOID:9007	OMIM:272120	J:193425

Genotype
MGI:4839498

cn22

• Allelic Composition: Vhl^tm1Jae/Vhl^tm1Jae; Tg(Cdh16-cre)91Igr/0
• Genetic Background: involves: 129S4/SvJae * ICR

reproductive system

abnormal epididymis morphology ( J:137442 )

♂ • aberrant presence of dilated blood capillaries surrounding epididymal tubules indicating increased vascularization

♂ • however, the genital tracts of males and females look normal

Genotype
MGI:4839497

cn23

• Allelic Composition: Pten^tm1Hwu/Pten^tm1Hwu; Vhl^tm1Jae/Vhl^tm1Jae; Tg(Cdh16-cre)91Igr/0
• Genetic Background: involves: 129S4/SvJae * ICR

reproductive system

abnormal oviduct morphology ( J:137442 )

♀ • cysts and squamous epithelial hyperplasia in the oviduct

endometrium hyperplasia ( J:137442 )

♀ • females exhibit hyperplasia and full squamous differentiation of the uterine endometrial lumen, endometrial hyperplasia, and endometrial hyperplasia with cyst formation

abnormal uterine cervix squamous epithelium morphology ( J:137442 )

♀ • cysts and squamous epithelial hyperplasia in the cervix

abnormal epididymis morphology ( J:137442 )

♂ • squamous metaplasia is seen in the epididymis

♂ • vascularization is increased in the epididymides

increased epididymal cystadenoma incidence ( J:137442 )

♂ • tumors contain regions of cystadenoma characterized by adenoid structures identical to human cystadenoma lesions arising in epididymides

♂ • cystadenoma display clear cell morphology

neoplasm

increased tumor incidence ( J:137442 )

• regions of squamous differentiation intermingle with the regions of cystadenoma

• cystadenomas appear to result from basal cell proliferation without differentiation, whereas regions of squamous metaplasia contain abundant basal cells in basal layers as well as cells with markers of epidermal differentiation

increased adenoma incidence ( J:137442 )

• all mutants develop benign mixed adenosquamous genital tract tumors (in epididymis, vesicular glands, vas deferens, endometrium, and oviduct) resembling clear cell cystadenomas that form in patients with Von Hippel-Lindau syndrome (VHL)

• tumors arise simultaneously in all genital tract epithelia and show expansion of basal cells

• endometrial hyperplasia with cyst formation resembles cystadenoma and cystic lesions seen in broad ligament of females with VHL

increased epididymal cystadenoma incidence ( J:137442 )

♂ • tumors contain regions of cystadenoma characterized by adenoid structures identical to human cystadenoma lesions arising in epididymides

♂ • cystadenoma display clear cell morphology

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
von Hippel-Lindau disease		DOID:14175	OMIM:193300	J:137442

Genotype
MGI:4459906

cx24

• Allelic Composition: Hif1a^tm1Rsjo/Hif1a^tm1Rsjo; Hif1an^tm1.2Rsjo/Hif1an^tm1.2Rsjo; Vhl^tm1Jae/Vhl^tm1Jae
• Genetic Background: involves: 129S1/Sv * 129S4/SvJae * 129X1/SvJ

cellular

cellular phenotype ( J:160941 )

N • proliferation of MEFs after 48 hours of culturing in normoxia or hypoxia conditions is normal