Phenotypes Associated with This Genotype

Genotype
MGI:5445155

• Allelic Composition: Crim1^{Gt(KST264)Byg}/Crim1^{Gt(KST264)Byg}
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6 * CD-1

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

mortality/aging

decreased survivor rate ( J:147543 )

• only 15% of outbred homozygotes reach birth and survive to adulthood

perinatal lethality, incomplete penetrance ( J:147543 )

• Background Sensitivity: outbreeding onto a CD-1 background for one generation results in only 15% of homozygotes recovered at birth

cardiovascular system

cardiovascular system phenotype ( J:147543 )

N • adult homozygotes exhibit normal anesthetized mean arterial pressure and left ventricle weight relative to wild-type controls

abnormal glomerular capillary endothelium morphology ( J:147543 )

• adult homozygotes exhibit thickening of the endothelial cells; however, the GBM is relatively normal

absent glomerular endothelium fenestra ( J:147543 )

• adult homozygotes exhibit loss of endothelial fenestrae

dilated glomerular capillary ( J:172334 )

• capillaries in both non-leaky and leaky glomeruli are significantly larger in diameter than those in wild type controls

• in leaky glomeruli the mean capillary diameter is 7-fold larger than that in non-leaky glomeruli

abnormal peritubular capillary morphology ( J:172334 )

• dextran labelling of plasma shows aneurism-like dilations of the peritubular vasculature in adult kidneys, unlike in wild-type controls

• peritubular vascular leakage is indicated by the presence of rhodamine B dextran in the interstitium surrounding the vasculature

• red blood cells within adult peritubular capillaries are widely spaced, unlike in wild-type controls

• however, the number, localization, and diameter of peritubular capillaries is not significantly altered

abnormal peritubular capillary endothelium morphology ( J:172334 )

• both juvenile (P18) and adult homozygotes show a thickened ruffled endothelial lining of peritubular capillaries with looping protrusions into the lumen

• endothelium shows separation from the basal lamina and reduced fenestration in many areas

• gaps in endothelium adjacent to an apparently normal basement membrane are occasionally observed

• endothelium disruption occurs prior to necrosis of surrounding tubule cells

increased vascular permeability ( J:172334 )

• adult homozygotes exhibit a leaky GFB and increased vascular permeability in other renal microvasculature, unlike wild-type controls

• live imaging reveals leakiness of both glomerular and peritubular capillaries

• variable degree of leakiness in individual glomeruli, with evidence of dextran filtration from the glomerular capillaries into the Bowman's space

renal/urinary system

renal/urinary system phenotype ( J:147543 , J:172334 )

N • adult homozygotes show no significant differences in left kidney weight and left kidney to body weight ratio or in 24-h urine, sodium, potassium, and osmolality excretion relative to wild-type controls (J:147543)

N • immunohistochemical analysis of adult kidneys shows normal peritubular capillary number and localization in the cortex and normal vasa recta staining in the inner medulla relative to wild-type controls (J:172334)

abnormal peritubular capillary morphology ( J:172334 )

• dextran labelling of plasma shows aneurism-like dilations of the peritubular vasculature in adult kidneys, unlike in wild-type controls

• peritubular vascular leakage is indicated by the presence of rhodamine B dextran in the interstitium surrounding the vasculature

• red blood cells within adult peritubular capillaries are widely spaced, unlike in wild-type controls

• however, the number, localization, and diameter of peritubular capillaries is not significantly altered

abnormal peritubular capillary endothelium morphology ( J:172334 )

• both juvenile (P18) and adult homozygotes show a thickened ruffled endothelial lining of peritubular capillaries with looping protrusions into the lumen

• endothelium shows separation from the basal lamina and reduced fenestration in many areas

• gaps in endothelium adjacent to an apparently normal basement membrane are occasionally observed

• endothelium disruption occurs prior to necrosis of surrounding tubule cells

increased kidney apoptosis ( J:187026 )

• TUNEL staining identifies apoptotic cells lining the adult renal pelvis

kidney cortex cyst ( J:147543 , J:187026 )

• adult kidneys display small cysts in the outer cortex (J:147543)

• MRI reveals extensive cortical cysts in adult kidneys (J:187026)

renal glomerulus cyst ( J:147543 , J:172334 , J:187026 )

• adult homozygotes exhibit large glomerular cysts (J:147543)

• large glomerular cysts of a diameter of 200 um are seen in adult, but not juvenile, kidneys (J:172334)

• adult hydronephrotic kidneys exhibit multiple glomerular cysts (J:187026)

albuminuria ( J:147543 )

• adult homozygotes show a 3-fold increase in 24-hr albumin excretion and albumin-to-creatinine excretion ratio relative to wild-type controls

kidney inflammation ( J:172334 )

• adult, but not juvenile, kidneys show upregulated markers of inflammation

impaired ureteric peristalsis ( J:187026 )

• a number of adult homozygotes show uncoordinated, non-productive pyeloureteric peristalsis with abnormal propagation of the initial contraction

• unlike in wild-type kidneys where peristaltic contractions initiated near the base of the papilla are circumferentially orientated and propagate distally along the longitudinal axis passing towards and into the ureter, the distal renal pelvis of mutant mice exhibits contractions in both the circular and the longitudinal direction almost synchronously with the ureter

• however, no significant difference in peristaltic frequency is noted between the two groups

• in addition, isolated renal pelvis preparations suggest normal pelvic smooth muscle contractile responses

increased glomerular capsule space ( J:147543 )

• cystic glomeruli exhibit an enlarged Bowman's space

podocyte foot process effacement ( J:147543 , J:172334 )

• adult homozygotes exhibit areas of podocyte flattening and effacement (J:147543)

• both juvenile (P18) and adult homozygotes show podocyte effacement, unlike wild-type controls (J:172334)

decreased renal glomerulus basement membrane thickness ( J:172334 )

• both juvenile (P18) and adult kidneys show a significant reduction in width of the basal lamina of the glomerular basement membrane, unlike wild-type controls

abnormal renal glomerulus morphology ( J:172334 )

• adult homozygotes show a significant increase in glomerulus diameter relative to wild-type controls

abnormal glomerular capillary endothelium morphology ( J:147543 )

• adult homozygotes exhibit thickening of the endothelial cells; however, the GBM is relatively normal

absent glomerular endothelium fenestra ( J:147543 )

• adult homozygotes exhibit loss of endothelial fenestrae

dilated glomerular capillary ( J:172334 )

• capillaries in both non-leaky and leaky glomeruli are significantly larger in diameter than those in wild type controls

• in leaky glomeruli the mean capillary diameter is 7-fold larger than that in non-leaky glomeruli

cortical renal glomerulopathies ( J:147543 )

• adult homozygotes exhibit glomerular obsolescence and collapse of the glomerular tuft, resembling collapsing glomerulopathy

glomerulosclerosis ( J:172334 )

• adult kidneys exhibit sclerotic glomeruli

• occasionally seen in juvenile (P21) kidneys

renal glomerulus hypertrophy ( J:147543 )

• adult homozygotes exhibit numerous enlarged glomeruli extending into the outer cortex

abnormal kidney corticomedullary boundary morphology ( J:187026 )

• MRI reveals a loss of corticomedullary differentiation in adult kidneys, unlike in wild-type controls where clear distinctions between the cortex, medulla, and papilla are observed

renal interstitial fibrosis ( J:147543 , J:172334 )

• adult kidneys exhibit areas of iinterstitial fibrosis (J:147543)

• adult kidneys show a significant increase in the % of collagen in both the cortex and the corticomedullary junction (J:172334)

• adult, but not juvenile (P21), kidneys exhibit extensive areas of fibrosis in the cortex involving sclerotic glomeruli and tubules, as well as in the medulla (J:172334)

abnormal kidney pelvis morphology ( J:187026 )

• TUNEL staining identifies apoptotic cells lining the adult renal pelvis

kidney papillary atrophy ( J:187026 )

• adult hydronephrotic kidneys exhibit atrophied papilla

kidney papillary hypoplasia ( J:187026 )

• juvenile (P4-P15) and adult homozygotes exhibit papillary hypoplasia

• homozygotes exhibit defects in papillary extension from the renal parenchyma in the immediate postnatal period (P0-P15)

short kidney papilla ( J:187026 )

• papillary length (normalized to kidney length) is significantly reduced relative to that in wild-type controls

• shortened papilla precede evidence of hydronephrosis and overt renal disease

hydronephrosis ( J:187026 )

• 27% of adult homozygotes (8-28 weeks of age) show evidence of progressive hydronephrosis associated with a dilated pelvis and atrophied papilla

small kidney ( J:187026 )

• juvenile (P4-P15) and adult mutant kidneys are on average 10% smaller than wild-type

dilated renal tubule ( J:147543 )

• adult homozygotes exhibit areas of renal tubular dilation

renal tubular necrosis ( J:172334 )

• adult (but not juvenile) homozygotes display regions of renal tubule necrosis

abnormal renal filtration rate ( J:187026 )

• dynamic contrast-enhanced MRI using a gadolinium-containing contrast agent (Gd-DTPA) reveals fast development of hypo-intense signal in mutant adult kidneys (7-8 weeks), indicating accumulation of Gd-DTPA within the renal parenchyma

• delayed urinary filtrate clearance occurs in all mutants examined, despite the absence of hydronephrosis, hydroureter or any evidence for a physical ureteric obstruction

• delayed rhodamine dextran (RD) clearance in juvenile (P21) mutant kidneys results in accumulation of tubular RD predominantly in collecting ducts of the medulla, indicating early onset of outflow obstruction at the collecting duct level

• functional obstruction occurs in all mice prior to P21, before overt hydronephrosis or progressive fibrosis

abnormal glomerular filtration barrier function ( J:172334 )

• adult homozygotes exhibit a leaky glomerular filtration barrier (GFB) that is permeable to FITC-Dextran (70 kDa), unlike wild-type controls

decreased renal glomerular filtration rate ( J:147543 )

• the GFR is 40% lower than that in adult wild-type controls

homeostasis/metabolism

albuminuria ( J:147543 )

• adult homozygotes show a 3-fold increase in 24-hr albumin excretion and albumin-to-creatinine excretion ratio relative to wild-type controls

abnormal renin activity ( J:172334 )

• adult, but not juvenile, kidneys show extraglomerular renin staining in pericytes in the afferent arteriole and in smooth muscle cells of larger arteries, indicating extensive recruitment of renin-producing cells

immune system

kidney inflammation ( J:172334 )

• adult, but not juvenile, kidneys show upregulated markers of inflammation

cellular

increased kidney apoptosis ( J:187026 )

• TUNEL staining identifies apoptotic cells lining the adult renal pelvis

abnormal basal lamina morphology ( J:172334 )

• both juvenile (P18) and adult kidneys show a significant reduction in width of the basal lamina of the glomerular basement membrane and the abluminal tubular basal lamina, unlike wild-type controls

hematopoietic system

hematopoietic system phenotype ( J:147543 )

N • adult homozygotes exhibit normal hematocrit values relative to wild-type controls

growth/size/body

growth/size/body region phenotype ( J:147543 )

N • adult homozygotes show no differences in body weight relative to wild-type controls

kidney cortex cyst ( J:147543 , J:187026 )

• adult kidneys display small cysts in the outer cortex (J:147543)

• MRI reveals extensive cortical cysts in adult kidneys (J:187026)

renal glomerulus cyst ( J:147543 , J:172334 , J:187026 )

• adult homozygotes exhibit large glomerular cysts (J:147543)

• large glomerular cysts of a diameter of 200 um are seen in adult, but not juvenile, kidneys (J:172334)

• adult hydronephrotic kidneys exhibit multiple glomerular cysts (J:187026)

muscle

impaired ureteric peristalsis ( J:187026 )

• a number of adult homozygotes show uncoordinated, non-productive pyeloureteric peristalsis with abnormal propagation of the initial contraction

• unlike in wild-type kidneys where peristaltic contractions initiated near the base of the papilla are circumferentially orientated and propagate distally along the longitudinal axis passing towards and into the ureter, the distal renal pelvis of mutant mice exhibits contractions in both the circular and the longitudinal direction almost synchronously with the ureter

• however, no significant difference in peristaltic frequency is noted between the two groups

• in addition, isolated renal pelvis preparations suggest normal pelvic smooth muscle contractile responses