Kidney Defects in Mutant Animals


Last revision – 9th July 2009

 

This table is part of the Kidney Development Database.

It concentrates on kidney defects which are 'developmental' in character and is not intended to include later pathologies
created through primary lesions in other systems. For example, mutations that unbalance the immune system and create
glomerulonephritic kidney damage are not included.


List of mutant tables (or just scroll);

 



 

Mutations affecting the embryo’s ability to form an MM at all.

 

Gene

Mutant type

Phenotype

Reference

 

 

 

 

Eya1

Knockout

No MM formed

Sagithlal G (2005)

PMID: 16018995 see also Xu (1999)
PMID: 10471511

Lim1

Knockout

No IM (or subsequent MM) formed

Shawlot (1995)

PMID: 7700351

Tsang (2000)

PMID: 10864462

Osr1

Knockout

No MM formed (ie none of the usual markers, Eya1, Six2, Pax2, Sall1 and Gdnf, can be found).

James (2006)

Pax2

Knockout

failure of mesonephros, metanephros & genital devpt; neither tubules or ureteric bud form; even heterozygote has small kidneys.

Torres (1995)

PMID: 8575306

 

 

 

Mutations affecting ureteric bud/collecting duct (see later table for mature ureter)

 

Gene

Mutant type

Phenotype

Reference

Agtr2

Knockout

Duplicated collecting system, abnormal ureteric budding

Oshima (2001)

PMID: 11586245

Alk3

Floxed Alk3, HoxB7cre-EGFP

Abnormal primary branch pattern, excess subsequent branching at first but then it reduces dramatically (to below normal). Hypoplastic medulla; abnormal expression of b-catenin and myc in medullary coll duct.

Hartwig S (2008)

PMID: 18178801

 

Bcl2

Knockout and HoxB7-knock-in rescue

Branching defect in knockout; rescued if bcl2 is re-expressed only in ub.

Kondo (2008)

PMID: 18729219

Dlgh1

Knockout

Ectopic ureteric buds, hypoplastic kidneys

Iizuka-Kogo (2007)

PMID: 17435047

Emx2

Knockout

UB forms but its tip never dilates, branching fails to happen

Miyamoto (1997)

PMID: 9165114

See also

Pellgerini (1996)

PMID: 9012509

Eya1

Knockout and hypomorphs

Failure of ub formation (secondary to problems in the MM so no GDNF made). UB formation but no branching in hypomorphs that yield 20% normal Eya1 levels

Sajithlal (2005)

PMID: 16018995 See also Xu (1999)

PMID: 10471511

FGF7

Knockout

kidneys smaller than +/+ wt; affecting both coll duct system size and nerhron number

Qiao (1999)

PMID: 9876183

FgfR1 AND 2 (double knockout)

Floxed fgfr1, floxed fgfr2, Pax3-cre

Ub forms but does not elongate or branch (but does express Ret and Pax2 normally)

Poladia (2006)

PMID: 16442091

Fgfr2

Conditional

Ectopic buds

Hains (2008)

PMID: 18670373

Fgfr2

knockout

Mis-patterned UB tree; too few tips

Zhao (2004)

PMID: 15581874

FoxC1

Knockout

Ectopic and duplex buds; gdnf region too anterior

Kume (2000)

PMID: 10704385

FoxD1 (=BF2)

knockout

hypoplastic; fused; c.d. small; too few nephrons; large mesenchymal condensates (Hatini) Mis-patterned UB tree, probably a tertiary effect of gene loss causing failure of capsule formation and consequent failure of organization of  BMP4-expressing mesenchymal cells that normally help pattern UB. (Levinson)

Hatini (1996)

PMID: 8666231

Levinson (2005)

PMID: 15634693

Fused mutation

Random

Variable failure of UB growth

Theiler (1956)

PMID: 13340237

Gata2

Hypomorph

Anteriorly-displaced ureteric budding and reduced BMP4 in intermediate mesenchyme derivatives.

Hoshino (2008)

PMID: 18233958

Gata3

floxed gata3,  HoxB7 cre

Multiple ectopic buds; some duplex kidneys, other defects. Phenotype may depend on FGF signalling

Grote (2008)

PMID: 19112489

GDNF

heterozygote

30% fewer neprhons; reduced extent of ureteric bud.

Cullen-McEwen (2001)

PMID: 11422733 and

PMID: 12574104

GDNF

knockout

renal agenesis due to lack of ureteric bud; can be rescued in vitro by added GDNF

Sanchez (1996)

PMID: 8657306

Pichel (1996)

PMID: 8657307

PMID: 9246473

Moore (1996)

PMID: 8657308

Sainio (1997)

PMID: 9374404

Glypican3

Heterozygote in various heterozygotes of BMP pathway components

Reduction of Gpc3 increases UB cell proliferation, probably due to reduced BMP sigalling

Hartwig (2005)

PMID: 15925496

Gremlin

knockout

Over-high pSmad in MM, GDNF/Wnt11 loop not set up properly,  ureteric outgrowth fails. Phenoptype is recuable by genetic reduction of BMP4

Michos (2007)

PMID: 17522159

Hs2ost

Knockout

no branching of ub; no condensation of mesenchyme

Bullock (1998)

PMID: 9637690

ICAT (=ctnnbip1)

Knockout

Delayed ub branching, then arrest of ub branching; renal agenesis

Hasegawa Y (2007)

PMID: 17803964

Integrin alpha 3

knockout

too few collecting duct branches; cystic proximal tubules

Kreidberg (1996)

PMID: 8951069

Integrin alpha 8

knockout

failure of ureteric bud growth; nephrons do not epithelialize

Muller (1997)

PMID: 9054500

Ld (limb deformity mutation – affects formins)

random

variable failure of ureteric bud growth

Maas (1994)

PMID: 7517224

Lgl1

heterozygote

20% reduction in ureteric bud branching

Quinlan J (2007)

PMID: 17670908

Lim1

Floxed Lim1, Pax2 cre

Formation of Ub delayed, ub branches too little and grows too little. WD dies back, MD fails even in females. Renal hypoplasia, hydronephrosis

Pedersen (2005)

PMID: 16216236

Also see Kobayashi (2005)

PMID: 15930111

Met

floxed Met, HoxB7 cre

Branching defect (too few), can be rescued partially by EGF

Ishibe (2009)

PMID: 19103805

Nephronectin

Knockout

UB delayed; renal agenesis/ hypoplasia; GDNF reduced dramatically (like alpha 8 integrin mutants)

Linton (2007)

PMID: 17537792

N-myc

Hypomorph

Collecting duct system hypoplasia

Bates (2000)

PMID: 10837121

R-cadherin

knockout

Odd morphology, elevated apoptosis

Dahl (2002)

PMID: 11839813

Ret

knockout

variable failure of ureteric bud invasion, growth & branching; MM can still be induced by spinal cord.

Pachnis (1993)

PMID: 8306871

Schuchardt (1994)

PMID: 8114940

Ret overexpression

driven by hox b7promoter (= expression throughout bud)

variable failure of ureteric bud growth & branching. (see paper - this summary is way too brief)

Srinivas (1999)

PMID: 10068631

Retinoic acid receptor (RAR) alpha / beta 1

Double knockout

impaired stromal function; poor ub branching. c-Ret down-regulated.

Mendelsohn (1999)

PMID: 10021334

Batourina (2001)

PMID: 11138002

Robo2

Knockout

Supernumerary buds, possibly because GDNF is maintained in appropriately anteriorly

Grieshammer (2004)

PMID: 15130495

Sall1

Knockout

MM fails to attract UB

Nishinakamura (2001)

PMID: 11688560

Sd (Danforth’s short tail) mutation

random

hypoplastic/aplastic kidneys (ureteric bud invasion inhibited

Gluecksohn-Schoenheimer (1943)

Slit2

Knockout

Supernumerary buds, possibly because GDNF is maintained in appropriately anteriorly

Grieshammer (2004)

PMID: 15130495

Sprouty1

knockout

Supernumerary buds, Irregular ub branching; tips larger and more numerous than controls. Increased wnt11 and gdnf expression. Cystic hyperplasia

Basson (2006)

PMID: 17022962 see also Basson (2005)

PMID: 15691764

TGFb

heterozygote

Extra generation of branches and longer branches

Sims-Lucas (2008)

PMID: 18317401

Wg (chicken wingless – is NOT connected to Drosophila Wg!)

random

Failure of ureteric bud invasion

secondary source:Ede 1978 -anyone know the primary source? (please mail me)

Wnt11

knockout

Too little ub branching; renal hypoplasia; GDNF levels too low

Majumdar A (2003)

PMID: 12783789

 



Mutations affecting the behaviour of MM, cap condensates and pre-tubular aggregates.

 

Gene

Mutant type

Phenotype

Reference

FgfR1 AND 2 (double knockout)

Floxed fgfr1, floxed fgfr2, Pax3-cre

Too much apoptosis and too little proliferation in MM. Six2, Pax2, Sall1 no activated (but Eya1 and Six1 are)

Poladia (2006)

PMID: 16442091

Hs2ost

Knockout

no branching of ub; no condensation of mesenchyme

Bullock (1998)

PMID: 9637690

Integrin alpha 8

knockout

nephrons do not epithelialized (and ub fails to grow properly)

Muller (1997)

PMID: 9054500

P53 over-expression

overexpression

hypoplastic; defective collecting duct diffn; high apoptosis of nephrogenic mesenchyme; 'inefficient conversion to tubules

Godley (1996)

PMID: 8846920

R-cadherin

knockout

Fewer tubules form

Dahl (2002)

PMID: 11839813

Sall1

Knockout

MM fails to attract UB

Nishinakamura (2001)

PMID: 11688560

Six2

knockout

Too much nephrogenesis at the expense of stem cell maintenance: cap mesenchyme lost as it all becomes nephrons

Self (2006)

PMID: 17036046

Shh

Knockout

MM dies

Yu (2002)

PMID: 12399320

Wnt4

knockout

Pretubular aggregates do not form (or form in very low numbers)

Stark (1994)

PMID: 7990960

See also Kispert (1998)

PMID: 9753677

Wt1

Knockout

MM cannot form nephrons, nor support bud growth, nor survive.

Kreidberg (1993)

PMID: 8395349

Wt1

siRNA inhibition

MM proliferates in response to ub but does not differentiate into nephrons

Davies (2004)

PMID: 14645201

 



Mutations affecting development of nephron epithelia (Renal vesicle onwards)

 

Gene

Mutant type

Phenotype

Reference

Bmp7

knockout

1. severe kid hypoplasia (lethal); early devpt OK (->E12.5), but then few nephrons form and cd branching ceases (Dudley & Luo)
2. adequate glomerulogenesis; well formed proximal tubule but poor distal tubules; polycystic (
Jena)

Dudley (1995)

PMID: 7590254

Luo (1995)

PMID: 7590255

Jena (1997)

PMID: 9013703

 

Cadherin6

knockout

many nephrons fail to fuse to the bud

Mah (2000)

PMID: 10864459

Epstein-Barr nuclear antigen 2

Transgenic expression of viral gene

Tubular hyperplasia then adenocarcinoma

Tornell (1996)

PMID: 8622868

Glucose-6-phosphatase

knockout

tubules enlarge at the expense of glomeruli

Lei (1996)

HNF1

knockout

Fanconi syndrome (proximal tubule dysfunction) during post-natal devt

Pontoglio (1996)

PMID: 8598044

Lim1

Floxed Lim1, Rarb2 cre

Nephrons arrest at renal vesicle

Kobayashi (2005)

PMID: 15930111

MALS-3

 

Apico-basal polarity defects especially in proximal tubules. Reflected in mislocation of CRB and DLG complexes in cells. Hypomorphic kidneys with numerous cysts.

Olsen (2007)

PMID: 17923534

 

 

 

Mutations affecting glomerular development (but later than the formation of a renal vesicle).

 

Gene

Mutant type

Phenotype

Reference

Collagen IV alpha 3

Knockout

Alport’s syndrome

Cosgrove (1996)

PMID: 8956999

Lmx1b

Knockout

Podocytes start to form but their foot processes are soon lost.

Witzgall (2008)

PMID: 18253764

Notch 2 (del1 allele)

knockout

hypoplasia; glomeruli do not develop fully

McRight (2001)

PMID: 11171333

Notch 2 (del1 allele) Jag-1 (dDSL allele)

double heterozygote

glomerular defects

McRight (2001)

PMID: 11171333

Uteroglobin

Knockout

FN-deposit glomerular disease

Zhang 1997

PMID: 9162006

 

 


Mutations affecting mainly vasculature

 

Gene

Mutant type

Phenotype

Reference

Angiotensinogen

knockout

Vessel walls thicken during post-natal development

Kim (1995)

PMID: 7708716

Gs-alpha

(part of adenylyl cyclase pathway)

Floxed GsAlpha, Ren1d cre

Renin expression absent; some differences in modelling of pre-glomerular arterial tree

Neubaueer (2009)

PMID: 19261741

PDGFb

Knockout

Very few glomeruli; absence of mesangial cells

Lindahl (1998)

PMID: 9693135

PDGFR

Knockout

No mesangial cells, probably because mesenchyme migration to PDGF sources messed up.

Ricono (2009)

PMID: 19019919

 

 

Mutations causing renal cysts

 

Gene

Mutant type

Phenotype

Reference

Bcl2-/-

knockout

polycystic disease; hypoplasia due to excess apoptosis during abnormal neprhogenesis

Veis (1993)

PMID: 8402909

Nagata (1996)

PMID: 8623928

Bmp4

heterozygote

polycystic during post-natal devt (Dunn)
hypo/dysplastic with uterovesical junction hydronephrosis; duplex kidney with bifid ureters like human CAKUT (
Miyazaki)

Dunn (1997)

PMID: 9268572

Miyazaki (2000)

PMID: 10749566

Dicer

floxed dicer, HoxB7cre

Cysts (collecting duct and nephron derived)

Pastorelli (2009)

PMID: 19169742

FGF7

Overexpression in LIVER (not kidney)

kidneys smaller than +/+ wt; affecting both coll duct system size and nerhron number

Nguyen (1996)

PMID: 8668336

Glypican-3

Knockout

Cystic collecting ducts

Cano-Gauci (1999)

PMID: 10402475

Integrin alpha 3

knockout

too few collecting duct branches; cystic proximal tubules

Kreidberg (1996)

PMID: 8951069

Inv mutant

random

Cystic kidneys

Mochizuki (1998)

PMID: 9744276

MALS-3

 

Apico-basal polarity defects especially in proximal tubules. Reflected in mislocation of CRB and DLG complexes in cells. Hypomorphic kidneys with numerous cysts.

Olsen (2007)

PMID: 17923534

Sprouty1

knockout

Irregular ub branching; tips larger and more numerous than controls. Increased wnt11 and gdnf expression. Cystic hyperplasia

Basson (2006)

PMID: 17022962

 

 

Mutations affecting ureter (& connection to bladder):

 

Gene

Mutant type

Phenotype

Reference

BMP4

Floxed BMP4

Poor ureteric muscle development, ureteropelvic junction obstruction

Wang 2008

PMID: 19010499

Dlgh1

Knockout

Wrongly orientated ureteric muscles, impaired peristalsis.

Mahoney (2006)

PMID: 17172448

Nfia

Knockout and heterozygote

Abnormalities of uretopelvic junction and uretovesical junction, megaureter

Lu (2007)

PMID: 17530927

Ptprs, Ptprf double mutant

knockout

Hydroureter, ureterocoele, possibly due to abnormally low cell death during morphogenesis: Ptprs inhibits Ret signalling

Uetani (2009)

PMID: 19273906

Tbx18

Knockout

Cells that should have been mesenchyme of ureter mislocate to surface of kidney; ones that remain don’t make muscle but make fibrous or ligamentous tissue instead. Short ureter; hydronephrosis.

Airik (2006)

PMID: 16511601

Tshz3

Knockout

Congenital hydronephrosis presumed due to absence of proximal smooth muscle cells

Caubit (2008)

PMID: 18776146

 

 

Other renal mutations

 

Gene

Mutant type

Phenotype

Reference

ACE

Knockout

Cortical thinning and atrophy in adulthood

Krege (1995)

PMID: 7753170

 

AP-2

knockout

hypoplastic; retarded devt of metanephros; many other defects in embryo

Zhang 1996

PMID: 8622766

COX-2 (cyclooxygenase)

knockout

poor bud devt apparent by birth; nephrons few and immature (E14 kidneys look OK )

Dinchuk (1995)

PMID: 7477380

FGF-R dominant negative - blocks aFGF, FGF3 & 7 not bFGF or FGF4

transgenic

no kidneys, or very small ones with vacuolated tubules

Celli (1998)

PMID: 9501086

Hexb

Knockout

vacuolation during post-natal devt

Phaneuf (1996)

PMID: 8789434

Os (oligosyndactly)

Heterzygote

hypoplasia in vivo & in culture

Sorenson (1996)

PMID: 8760267

P57

Knockout

medullary dysplasia like Beckwith-Wiedemann syndrome

Zhang (1997)

PMID: 9144284