Mouse Genome Informatics
hm
    Pkd1tm1Jzh/Pkd1tm1Jzh
either: (involves: 129S4/SvJae * C57BL/6) or (involves: 129S4/SvJae * BALB/c)
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• after E18.5, most mutant embryos are dead, partly absorbed or misshapen
• few homozygotes survive to term but die, on average, 4 hours after birth
• only 1 out of 400 homozygotes survived the neonatal period and died at P8 with pale cystic kidneys and a cystic pancreas

cardiovascular system
N
• homozygotes exhibit normal fetal hearts relative to wild-type mice (J:72627)

digestive/alimentary system
• homozygotes show early and massive dilatation of pancreatic ducts

endocrine/exocrine glands
N
• homozygotes exhibit no cyst formation in testis, ovary or salivary glands (J:43193)
• homozygotes show early and massive dilatation of pancreatic ducts
• homozygotes contain fewer islets of Langerhans than wild-type mice; in contrast, acini appear to develop normally
• homozygotes exhibit cysts in major pancreatic ducts as early as E13.5, before renal cysts develop
• newborn (and P8) pancreases contain massive yellow fluid-filled cysts that enlarge with age

growth/size
• at P8, the sole mutant survivor is significantly smaller relative to wild-type (J:43193)
• newborn homozygotess exhibit dwarfism relative to newborn wild-type mice (J:72627)
• homozygotes that die perinatally display distended abdomens

hematopoietic system
N
• homozygotes display no changes in hemoglobin levels or erythrocyte morphology relative to wild-type (J:72627)

homeostasis/metabolism
• exhibit mild hydrops fetalis at late stages of fetal development
• histologically, mutant fetuses exhibit a mild subcutaneous edema
• exhibit mild polyhydramnios at late stages of fetal development

liver/biliary system
N
• unlike patients with ADPKD, homozygotes display no liver cyst formation (J:43193)

renal/urinary system
N
• in mutants, the initial stages of lumen formation and tubule differentiation proceed normally as late as E15.5 (J:43193)
• in culture, kidney epithelial cells isolated from E15.5 (pre-cystic) mutant mice form primary cilia but fail to increase Ca2+ influx in response to physiological fluid flow at low levels of fluid shear stress (0.75 dyne cm-2)
• no Ca2+ signaling is detected in wild-type or mutant cells at higher levels of fluid shear stress (15 dyne cm-2)
• both wild-type and mutant cells respond to thrombin by increasing cytosolic Ca2+ concentrations, indicating that mutant cells retain the ability to conduct Ca2+ but lose the ability to sense fluid flow
• the Ca2+ response to thrombin is enhanced in mutant cells relative to wild-type cells, either in the presence of extracellular Ca2+
• by P8, renal parencyma in the sole survivor is almost completely replaced by cysts; cuboidal tubular epithelia are replaced by flattened cyst-lining epithelia
• homozygotes that die perinatally exhibit massive kidney enlargement
• in newborn homozygotes, tubule dilatation is more extensive, affecting most of the kidney
• at E15.5, homozygotes display progressive multifocal microdilatation of tubules in proximal tubules of the outer medulla
• homozygotes that die perinatally first exhibit tubular and periglomerular cysts at E15.5; no histological abnormalities are noted until E14.5 (J:43193)
• the number and size of cysts increase with age (J:43193)
• after E15.5, progressive tubule dilatation and cyst formation is noted in mutant cortex
• in newborn homozygotes, epithelial cysts occupy most of the cortex
• at E15.5, tubular and periglomerular cysts are scattered throughout the outer medulla; nephrogenesis at the rim of the kidney remains unaffected
• cyst formation is subsequently noted in collecting tubules of the inner medulla
• in newborn homozygotes, epithelial cysts occupy the entire medulla

respiratory system
• a number of newborn homozygotes exhibit thyroid cartilage malformation
• homozygotes that die perinatally have small lungs relative to wild-type mice
• homozygotes that die perinatally have hypoplastic lungs
• homozygotes that survive to term but die perinatally exhibit difficulty in breathing and fail to turn pink

skeleton
• 8 out of 11 (73%) homozygotes develop mild spina bifida occulta in the lumbar region at late embryonic or newborn stages
• a number of newborn homozygotes exhibit thyroid cartilage malformation
• newborn homozygotes display osteochondrodysplasia
• newborn homozygotes display a delay in bone mineralization of vertebrae, long bones and skull relative to wild-type mice

nervous system
• 8 out of 11 (73%) homozygotes develop mild spina bifida occulta in the lumbar region at late embryonic or newborn stages

embryogenesis
• 8 out of 11 (73%) homozygotes develop mild spina bifida occulta in the lumbar region at late embryonic or newborn stages

integument
• histologically, mutant fetuses exhibit a mild subcutaneous edema

cellular
• in culture, kidney epithelial cells isolated from E15.5 (pre-cystic) mutant mice form primary cilia but fail to increase Ca2+ influx in response to physiological fluid flow at low levels of fluid shear stress (0.75 dyne cm-2)
• no Ca2+ signaling is detected in wild-type or mutant cells at higher levels of fluid shear stress (15 dyne cm-2)
• both wild-type and mutant cells respond to thrombin by increasing cytosolic Ca2+ concentrations, indicating that mutant cells retain the ability to conduct Ca2+ but lose the ability to sense fluid flow
• the Ca2+ response to thrombin is enhanced in mutant cells relative to wild-type cells, either in the presence of extracellular Ca2+

Mouse Models of Human Disease
OMIM IDRef(s)
Polycystic Kidney Disease 1; PKD1 173900 J:43193 , J:72627 , J:81443