Phenotypes associated with this allele

• Allele Symbol: Gdnf^tm1Lmgd
• Allele Name: targeted mutation 1, Laboratory of Mammalian Genes and Development, Heiner Westphal
• Allele ID: MGI:2136846
• Summary: 6 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Gdnf^tm1Lmgd/Gdnf^tm1Lmgd	either: (involves: 129S4/SvJae) or (involves: 129S1/Sv * 129X1/SvJ)	MGI:3588431
ht2	Gdnf^tm1Lmgd/Gdnf^+	B6.129-Gdnf^tm1Lmgd	MGI:5288237
ht3	Gdnf^tm1Lmgd/Gdnf^+	either: (involves: 129S4/SvJae) or (involves: 129S1/Sv * 129X1/SvJ)	MGI:3588433
ht4	Gdnf^tm1Lmgd/Gdnf^+	either: (involves: 129/Sv) or (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * CD-1)	MGI:3588490
ht5	Gdnf^tm1Lmgd/Gdnf^+	involves: 129/Sv * C57BL/6	MGI:5287873
cx6	Gdnf^tm1Lmgd/Gdnf^+ Kif26b^tm1.1Ryn/Kif26b^+	involves: 129 * C57BL/6 * C57BL/6J * CBA	MGI:4459954

Genotype
MGI:3588431

hm1

• Allelic Composition: Gdnf^tm1Lmgd/Gdnf^tm1Lmgd
• Genetic Background: either: (involves: 129S4/SvJae) or (involves: 129S1/Sv * 129X1/SvJ)

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

mortality/aging

neonatal lethality, complete penetrance ( J:33810 )

• die 12-24 hours after birth

renal/urinary system

abnormal kidney development ( J:33810 )

• severe renal dysgenesis or renal agenesis

• metanephric development is halted between E11 and E14.5

absent kidney ( J:33810 )

impaired branching involved in ureteric bud morphogenesis ( J:33810 )

• delayed or total absence of ureteric branching in cultured urogenital blocks

absent ureteric bud ( J:33810 )

• ureteric bud is absent in most mice

nervous system

abnormal enteric cholinergic neuron morphology ( J:33810 )

• devoid of enteric parasympathetic cholinergic ganglion cells

absent enteric neurons ( J:33810 )

• neurons of the myenteric plexus are absent from the intestine

digestive/alimentary system

intestinal hypoperistalsis ( J:33810 )

• presence of milk in the oesophagus and reduced progression of food into the gastrointestinal tract

muscle

intestinal hypoperistalsis ( J:33810 )

• presence of milk in the oesophagus and reduced progression of food into the gastrointestinal tract

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Hirschsprung's disease		DOID:10487	OMIM:600156 OMIM:606874 OMIM:606875 OMIM:608462 OMIM:611644	J:33810

Genotype
MGI:5288237

ht2

• Allelic Composition: Gdnf^tm1Lmgd/Gdnf⁺
• Genetic Background: B6.129-Gdnf^tm1Lmgd

renal/urinary system

renal/urinary system phenotype ( J:103081 , J:168650 )

N • at 14 months of age, no significant differences in GFR, renal blood flow, renal vascular resistance, filtration fraction, fractional sodium and potassium excretions, urinary protein concentration, and kidney weight or volume are observed (J:103081)

N • at 26 weeks of age, heterozygotes show normal renal innervation relative to wild-type controls (J:168650)

N • at 26 weeks, lower nephron number is not accompanied by changes in intrarenal arteries or peritubular capillaries or by altered distribution of tubular transporters (J:168650)

increased kidney cell proliferation ( J:168650 )

• at 26 weeks of age, glomerular cell proliferation is significantly higher than that in wild-type controls

kidney cortex cyst ( J:103081 )

• at 14 months of age, one kidney displayed a cortical cyst

tubulointerstitial nephritis ( J:103081 )

• at 14 months of age, one kidney displayed areas of focal interstitial inflammation

abnormal renal corpuscle morphology ( J:103081 )

• at 14 months of age, mean renal corpuscle volume is 30% larger than in wild-type kidneys; however, total glomerular and renal corpuscle volumes remain unaffected

abnormal glomerular capillary endothelium morphology ( J:168650 )

• at 26 weeks of age, the number of endothelial cells per glomerulus is significantly increased relative to that in wild-type controls; however, endothelial cells are not hypertrophic

decreased glomerular capillary number ( J:168650 )

• at 26 weeks of age, glomerular capillary density i.e. capillary length per glomerular volume is significantly reduced (-14%) relative to that in wild-type controls; however, the total length of glomerular capillaries per kidney is normal

increased mesangial cell number ( J:168650 )

• at 26 weeks of age, the number of mesangial cells per glomerulus is significantly increased relative to that in wild-type controls; however, mesangial cells are not hypertrophic

abnormal podocyte morphology ( J:168650 )

• at 26 weeks of age, enlargement of podocytes with increased cytoplasmic vacuolization is observed

• a slightly higher desmin positivity suggests mild podocyte damage

fused podocyte foot processes ( J:168650 )

• at 26 weeks of age, partial fusion of foot processes is observed

decreased podocyte number ( J:168650 )

• at 26 weeks of age, the podocyte number per area is significantly lower (-30%) than that in wild-type controls, indicating podocyte rarefaction

increased renal glomerulus basement membrane thickness ( J:168650 )

• at 26 weeks of age, significant thickening of the GBM is observed relative to wild-type controls

decreased renal glomerulus number ( J:103081 )

• at 14 months of age, heterozygotes contain ~30% fewer glomeruli than wild-type mice

renal glomerulus hypertrophy ( J:103081 , J:168650 )

• at 14 months of age (but not at P30), glomeruli of heterozygous kidneys are 20% larger than those of wild-type kidneys; however, no evidence of sclerosis or hypercellularity is observed (J:103081)

• at 26 weeks of age, mean glomerular volume is significantly higher (+49.5%) than in wild-type controls; however, total glomerular volume is comparable between the groups (J:168650)

renal interstitial fibrosis ( J:168650 )

• at 26 weeks of age, the % of interstitial fibrous tissue is significantly higher than in wild-type controls, indicating early interstitial activation

• however, no proinflammatory or prohypertensive changes are observed in the kidney

decreased kidney weight ( J:168650 )

• at 26 weeks of age, absolute and relative kidney weights are significantly lower than in wild-type controls

increased compensatory renal growth ( J:168650 )

• in heterozygotes with a single kidney, a compensatory higher volume of the single kidney is seen at 26 weeks, so that the relative total kidney weight is similar to that in mice with two kidneys

decreased nephron number ( J:103081 , J:168650 )

• at 26 weeks of age, nephron number is reduced by 32.8% relative to that in wild-type controls (J:168650)

♂ • at 14 months of age, male heterozygotes exhibit ~30% fewer nephrons than wild-type mice (J:103081)

abnormal renal tubule morphology ( J:103081 )

• at 14 months of age, heterozygotes display greater and more widespread renal tubular vacuolation than wild-type mice; however, no signs of tubular necrosis or apoptosis are observed

single kidney ( J:168650 )

• at 26 weeks of age, 5 of 11 female and 2 of 11 male heterozygotes exhibit unilateral renal agenesis

cardiovascular system

cardiovascular system phenotype ( J:168650 )

N • at 26 weeks of age, heterozygotes show no significant differences in mean arterial pressure or relative heart weight compared to wild-type controls

abnormal glomerular capillary endothelium morphology ( J:168650 )

• at 26 weeks of age, the number of endothelial cells per glomerulus is significantly increased relative to that in wild-type controls; however, endothelial cells are not hypertrophic

decreased glomerular capillary number ( J:168650 )

• at 26 weeks of age, glomerular capillary density i.e. capillary length per glomerular volume is significantly reduced (-14%) relative to that in wild-type controls; however, the total length of glomerular capillaries per kidney is normal

increased mean systemic arterial blood pressure ( J:103081 )

• at 14 months of age, anesthetized heterozygotes display a 18 mm Hg increase in mean arterial pressure relative to wild-type littermates

immune system

tubulointerstitial nephritis ( J:103081 )

• at 14 months of age, one kidney displayed areas of focal interstitial inflammation

cellular

increased mesangial cell number ( J:168650 )

• at 26 weeks of age, the number of mesangial cells per glomerulus is significantly increased relative to that in wild-type controls; however, mesangial cells are not hypertrophic

increased kidney cell proliferation ( J:168650 )

• at 26 weeks of age, glomerular cell proliferation is significantly higher than that in wild-type controls

growth/size/body

kidney cortex cyst ( J:103081 )

• at 14 months of age, one kidney displayed a cortical cyst

Genotype
MGI:3588433

ht3

• Allelic Composition: Gdnf^tm1Lmgd/Gdnf⁺
• Genetic Background: either: (involves: 129S4/SvJae) or (involves: 129S1/Sv * 129X1/SvJ)

renal/urinary system

abnormal kidney morphology ( J:33810 )

• 35% possess a wide range of renal defects between 3 to 5 months of age

abnormal kidney development ( J:33810 )

• 12% have severe bilateral kidney dysgenesis

small kidney ( J:33810 )

• 23% have unilateral small kidneys

single kidney ( J:33810 )

• 23% have unilateral small kidneys with abnormal shape and/or cortical cysts or rough surface

abnormal ureteric bud morphology ( J:33810 )

• ureteric bud defects

impaired branching involved in ureteric bud morphogenesis ( J:33810 )

• reduced ureteric branching in cultured urogenital blocks

Genotype
MGI:3588490

ht4

• Allelic Composition: Gdnf^tm1Lmgd/Gdnf⁺
• Genetic Background: either: (involves: 129/Sv) or (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * CD-1)

mortality/aging

preweaning lethality, incomplete penetrance ( J:73922 )

• low, but highly significant, preweaning lethality

• Background Sensitivity: 17.1% preweaning lethality on the C57BL/6 background and 8.4% preweaning lethality on the CD-1 background which increased to 16.7% after interbreeding of offspring on the CD-1 background

renal/urinary system

single kidney ( J:73922 )

• 10% exhibit unilateral kidney agenesis

nervous system

abnormal enteric ganglia morphology ( J:73922 )

• 64% reduction of ganglionic cells in the ileocecum and colon and 50% reduction in the stomach and small intestine

• exhibit aganglionic regions interspersed along the hypoganglionic regions of the intestine

abnormal myenteric nerve plexus morphology ( J:73922 )

• hypoganglionisis, as indicated by reduced numbers and mesh density of ganglionic cells in both the myenteric and the submucosal plexus formations of the gastrointestinal tract

abnormal submucous nerve plexus morphology ( J:73922 )

• hypoganglionisis, as indicated by reduced numbers and mesh density of ganglionic cells in both the myenteric and the submucosal plexus formations of the gastrointestinal tract

digestive/alimentary system

megacolon ( J:73922 )

• 84% have varying degrees of colon dilation

distended stomach ( J:73922 )

• 38.5% exhibit stomach distention

chronic constipation ( J:73922 )

• 74% exhibit fecal retention, a sign of chronic constipation

intestinal hypoperistalsis ( J:73922 )

• delayed gastric emptying of milk in newborns, indicating impaired intestinal motility

muscle

intestinal hypoperistalsis ( J:73922 )

• delayed gastric emptying of milk in newborns, indicating impaired intestinal motility

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Hirschsprung's disease		DOID:10487	OMIM:600156 OMIM:606874 OMIM:606875 OMIM:608462 OMIM:611644	J:73922

Genotype
MGI:5287873

ht5

• Allelic Composition: Gdnf^tm1Lmgd/Gdnf⁺
• Genetic Background: involves: 129/Sv * C57BL/6

renal/urinary system

increased kidney weight ( J:103800 )

• heterozygous mice with a single kidney show increased kidney weight relative to sex-matched wild-type mice

abnormal renal corpuscle morphology ( J:103800 )

• at P30, heterozygous mice show a significant decrease in the total volume of glomeruli and renal corpuscles relative to wild-type mice

• however, one female with unilateral agenesis showed normal glomerular and renal corpuscle volume

decreased renal glomerulus number ( J:103800 )

• at P30, glomerular number is ~30% less than in wild-type mice

small kidney ( J:103800 )

• at P30, mean kidney weight and volume in heterozygous mice are~ 25% smaller than in sex-matched wild-type mice

decreased nephron number ( J:103800 )

• at P30, heterozygous kidneys contain ~30% fewer nephrons than wild-type

• however, one female with unilateral agenesis displayed a normal nephron number

single kidney ( J:103800 )

• 14.6% of heterozygous mice are born with unilateral kidney agenesis

impaired branching involved in ureteric bud morphogenesis ( J:103800 )

• at P30, nephron number is decreased, presumably due to reduced branching morphogenesis of the ureteric bud

• the absolute ureteric duct volume is decreased by 24% relative to that in wild-type mice

• however, one female with unilateral agenesis displayed greater absolute and relative ureteric duct volumes than wild-type mice

growth/size/body

growth/size/body region phenotype ( J:103800 )

N • at P30, heterozygous mice display normal body weights relative to wild-type mice

increased kidney weight ( J:103800 )

• heterozygous mice with a single kidney show increased kidney weight relative to sex-matched wild-type mice

Genotype
MGI:4459954

cx6

• Allelic Composition: Gdnf^tm1Lmgd/Gdnf⁺; Kif26b^tm1.1Ryn/Kif26b⁺
• Genetic Background: involves: 129 * C57BL/6 * C57BL/6J * CBA

renal/urinary system

renal hypoplasia ( J:160285 )

• more mice exhibit kidney hypoplasia than in either heterozygous mice

absent kidney ( J:160285 )

• more mice exhibit kidney agenesis than in either heterozygous mice