C57BL/6J-Wt1^Vih/H

Status	Available to order
EMMA ID	EM:15813
Citation information	RRID:IMSR_EM:15813 Research Resource Identifiers (RRID) are persistent unique ID numbers assigned to help researchers cite key resources (e.g. antibodies, model organisms and software projects) in the biomedical literature to improve transparency and reproducibility in research. See https://www.rrids.org/ for more information.
International strain name	C57BL/6J-Wt1^Vih/H
Alternative name	Wt1R394W/+
Strain type	Targeted Mutant Strains
Allele/Transgene symbol	Wt1^R394W
Gene/Transgene symbol	Wt1

Information from provider

Provider	Vicki Huff
Provider affiliation	Department of Genetics, The University of Texas MD Anderson Cancer Center
Genetic information	This strain models human Denys-Drash Syndrome (DDS) when on an MF1 background. When male heterozygous mice are back-crossed onto female MF1 for 2 generations, male mice show key phenotypes of glomerular disease including albuminuria, glomerular scarring, renal failure. This is a strong phenocopy of human Denys Drash syndrome. Female mice show a much slower renal disease so are not used for kidney research, but they are infertile due to issues with granulosa cell differentiation The R394W mutation is the most common mutation found in human DDS. The R394W mutation was introduced into mouse embryonic stem (ES) cells by homologous recombination by a cre-loxP strategy (Fig. 1A). With a genomic Wt1 clone isolated from a 129/SvEv genomic library, a loxP-PGKneobpA-loxP cassette was inserted in reverse orientation 3′ of exon 9 and an MC1tkpA herpes simplex virus thymidine kinase expression cassette (Citation26, Citation41) was introduced 3′ of exon 10 of Wt1. The C1180T mutation was introduced via site-directed mutagenesis, and the entire construct was sequenced to verify the presence of the C-to-T transition and to ensure that no other alteration had been introduced into the construct. AB1 (129/SvEv) ES cells were electroporated with the Wt1R394W targeting construct and selected for resistance to G418 and sensitivity to 1-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)-s-iodouracil (Citation26, Citation27). Clones were genotyped by Southern blotting of EcoRV-restricted clone DNA hybridized to a genomic probe 5′ of exon 7 (5′ probe); introduction of the neo cassette by homologous recombination resulted in a 7.14-kb fragment compared to the normal 5.34-kb fragment (Fig. 1B). Following sequence verification, a targeted ES cell clone was injected into C57BL/6 (B6) blastocysts. Male chimeras were identified by coat color and subsequently crossed with wild-type females. Tail biopsies from agouti-pigmented F1 animals were genotyped by PCRs with a common forward primer (1.47 [5′ CTG CAG GTG GCT GTA CAG AA 3′]) paired with a mutant allele-specific primer (1.46 [5′ GTC TTC AGA TGG TCG GTC CA 3′]) (Fig. 1D). Wt1+/R394W-neo offspring were crossed with ZP3-cre (Jackson Laboratory) females. Offspring were assessed for the excision of the neo cassette, and several Wt1+/R394W heterozygotes were identified.
Phenotypic information	Homozygous: homozygous mice are embryonic lethal. https://doi.org/10.1128/MCB.24.22.9899-9910.2004 Heterozygous: Heterozygous mice show no phenotype on C57BL/6, but when male hets are back-crossed onto female MF1 for 2 generations the male hets show key phenotypes of glomerular disease (albuminuria, glomerular scarring, renal failure). This is a strong phenocopy of human Denys-Drash syndrome. The R394W mutation is the most common mutation found in human DDS. Please see https://doi.org/10.1128/MCB.24.22.9899-9910.2004 for generation of line and characterisation Please see https://doi.org/10.1002/path.6339 for more on disease phenotype Female mice show a much slower renal disease so are not used for kindey research, but they are infertile due to issues with granulosa cell differentiation. Please see DOI: 10.1093/hmg/ddt423
Breeding history	This line is maintained on C57BL/6 but is then backcrossed for 2 generations onto MF1 for disease phenotype.
References	Single-cell transcriptomics identifies aberrant glomerular angiogenic signalling in the early stages of WT1 kidney disease.;Chandler Jennifer C, Jafree Daniyal J, Malik Saif, Pomeranz Gideon, Ball Mary, Kolatsi-Joannou Maria, Piapi Alice, Mason William J, Benest Andrew V, Bates David O, Letunovska Aleksandra, Al-Saadi Reem, Rabant Marion, Boyer Olivia, Pritchard-Jones Kathy, Winyard Paul J, Mason Andrew S, Woolf Adrian S, Waters Aoife M, Long David A, ;2024;The Journal of pathology;264;212-227; 39177649 The Wt1+/R394W mouse displays glomerulosclerosis and early-onset renal failure characteristic of human Denys-Drash syndrome.;Gao Fei, Maiti Sourindra, Sun Guizhi, Ordonez Nelson G, Udtha Malini, Deng Jian Min, Behringer Richard R, Huff Vicki, ;2004;Molecular and cellular biology;24;9899-910; 15509792
Homozygous fertile	no
Homozygous viable	no
Homozygous matings required	no
Immunocompromised	no

Information from EMMA

Archiving centre	Mary Lyon Centre at MRC Harwell, Oxford, United Kingdom

Disease and phenotype information

Orphanet associated rare diseases, based on orthologous gene matching

Nephroblastoma / Orphanet_654
Denys-Drash syndrome / Orphanet_220
Meacham syndrome / Orphanet_3097
Frasier syndrome / Orphanet_347
Genetic steroid-resistant nephrotic syndrome / Orphanet_656

MGI phenotypes (gene matching)

abnormal heart development / MGI
abnormal heart shape / MGI
kidney cortex cysts / MGI
abnormal kidney development / MGI
abnormal kidney blood vessel morphology / MGI
abnormal liver development / MGI
liver hypoplasia / MGI
absent spleen / MGI
small testis / MGI
abnormal lung development / MGI
pulmonary hypoplasia / MGI
decreased embryo size / MGI
edema / MGI
abnormal reproductive system physiology / MGI
male infertility / MGI
prenatal lethality / MGI
premature death / MGI
abnormal embryonic tissue morphology / MGI
no abnormal phenotype detected / MGI
small heart / MGI
decreased germ cell number / MGI
abnormal secondary sex determination / MGI
streak gonad / MGI
dilated renal tubules / MGI
glomerulonephritis / MGI
increased urine protein level / MGI
small kidney / MGI
primary sex reversal / MGI
renal interstitial fibrosis / MGI
absent ovary / MGI
kidney failure / MGI
kidney cysts / MGI
diaphragmatic hernia / MGI
azoospermia / MGI
hemopericardium / MGI
glomerulosclerosis / MGI
absent adrenal gland / MGI
abnormal renal glomerulus morphology / MGI
abnormal podocyte morphology / MGI
abnormal mesangial cell morphology / MGI
renal/urinary system phenotype / MGI
cardiovascular system phenotype / MGI
agonadal / MGI
abnormal mesenchyme morphology / MGI
absent testes / MGI
absent podocyte foot process / MGI
podocyte foot process effacement / MGI
increased splenocyte apoptosis / MGI
abnormal spleen development / MGI
myocardium hypoplasia / MGI
primary atelectasis / MGI
neonatal lethality, complete penetrance / MGI
perinatal lethality, complete penetrance / MGI
embryonic lethality, complete penetrance / MGI
lethality throughout fetal growth and development, complete penetrance / MGI
prenatal lethality, incomplete penetrance / MGI
embryonic lethality during organogenesis, incomplete penetrance / MGI
juxtaglomerular cell hyperplasia / MGI
abnormal kidney interlobular artery morphology / MGI
abnormal glomerular capillary morphology / MGI
expanded mesangial matrix / MGI
absent metanephros / MGI
increased metanephric mesenchyme apoptosis / MGI
renal cast / MGI
increased renal glomerulus basement membrane thickness / MGI
abnormal gonadal ridge morphology / MGI
mesangial cell hyperplasia / MGI
mesangiolysis / MGI
abnormal glomerular capsule parietal layer morphology / MGI
decreased glomerular capsule space / MGI
glomerular crescent / MGI
podocyte microvillus transformation / MGI
podocyte hypertrophy / MGI
abnormal diaphragm development / MGI
abnormal pleuropericardial membrane morphology / MGI
abnormal heart apex morphology / MGI
abnormal adrenal gland development / MGI

Literature references

Single-cell transcriptomics identifies aberrant glomerular angiogenic signalling in the early stages of WT1 kidney disease.;Chandler Jennifer C, Jafree Daniyal J, Malik Saif, Pomeranz Gideon, Ball Mary, Kolatsi-Joannou Maria, Piapi Alice, Mason William J, Benest Andrew V, Bates David O, Letunovska Aleksandra, Al-Saadi Reem, Rabant Marion, Boyer Olivia, Pritchard-Jones Kathy, Winyard Paul J, Mason Andrew S, Woolf Adrian S, Waters Aoife M, Long David A, ;2024;The Journal of pathology;264;212-227; 39177649
The Wt1+/R394W mouse displays glomerulosclerosis and early-onset renal failure characteristic of human Denys-Drash syndrome.;Gao Fei, Maiti Sourindra, Sun Guizhi, Ordonez Nelson G, Udtha Malini, Deng Jian Min, Behringer Richard R, Huff Vicki, ;2004;Molecular and cellular biology;24;9899-910; 15509792

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C57BL/6J-Wt1Vih/H