Phenotypes Associated with This Genotype

Genotype
MGI:3617451

• Allelic Composition: Pkd2^tm1Som/Pkd2^tm2Som
• Genetic Background: involves: 129/Sv * C57BL/6J * SJL

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

mortality/aging

premature death ( J:59314 )

• median survival time is 65 weeks compared to 94.1 weeks for wild-type

renal/urinary system

increased kidney apoptosis ( J:158354 )

• in cystic renal epithelia cells, apoptotic indices are gradually increased from ~13.55% at 5-8 months of age to ~21.02% at 9-12-months of age, unlike in wild-type cells (~2.86%)

increased kidney cell proliferation ( J:158354 )

• at 5-8 months of age, ~2.86% nuclei of cystic renal epithelial cells are PCNA-positive relative to ~0.85% in wild-type cells; like in hepatic cysts, the % of PCNA-positive nuclei does not change significantly (~2.55%) with age

polycystic kidney ( J:47035 , J:59314 , J:158354 , J:220561 )

• all have bilateral renal cysts (J:47035)

• exhibit renal cyst formation by 6-10 weeks of age that progresses to cystic replacement of normal renal parenchyma later in life (J:59314)

• numerous macroscopically visible cysts are scattered on the kidney surface at an early disease stage (J:158354)

• total renal cystic volume decreases from ~ 40.67% of total kidney parenchyma at 5-8 months to ~31.04% at 9-12 months of age (J:158354)

• primary cilia in cystic renal epithelial cells remain normal despite a tendency to be shorter (J:158354)

• no significant fibrosis is noted around renal cysts in either age group (J:158354)

• mice show a similar level of polycystic kidney disease as single Pkd1^tm1.1Pcha homozygotes (J:220561)

enlarged kidney ( J:158354 )

• mutant kidneys are enlarged with numerous macroscopically visible cysts

increased kidney weight ( J:158354 , J:220561 )

• at 5-8 months of age, mutant kidney weights represent ~2% of total body weight (J:158354)

• by 9-12 months of age, mutant kidney weights account for ~2.6% of total body weight (J:158354)

• kidney weight to body weight ratio is increased to the same extent as in single Pkd1^tm1.1Pcha homozygotes (J:220561)

kidney failure ( J:59314 )

liver/biliary system

increased cholangiocyte apoptosis ( J:158354 )

• at 5-8 months of age, apoptotic indices in cystic cholangiocytes are increased to ~3.41% relative to ~0.56% in wild-type cholangiocytes, but do not change significantly with age (~3.86% at 9-12 months)

abnormal cholangiocyte morphology ( J:158354 )

• cystic cholangiocytes lining intrahepatic bile ducts are enlarged with a thickened basement membrane and a significantly larger width (i.e. distance between two cell junctions) relative to wild-type cholangiocytes

• most cystic cholangiocytes are squamous in appearance

abnormal cholangiocyte primary cilium morphology ( J:158354 )

• cystic cholangiocyte cilia are ~2-fold shorter than wild-type

• ~25% of primary cilia in cystic cholangiocytes appear malformed (e.g. bulbs at the ciliary tip)

bile duct proliferation ( J:47035 , J:158354 )

• 3 of 6 have bile duct proliferation (J:47035)

• at 5-8 months of age, ~18.77% nuclei of cystic cholangiocytes are PCNA-positive relative to ~1.12% in wild-type cholangiocytes; however, the % of PCNA-positive nuclei does not change significantly with age (~20.26% at 9-12 months) (J:158354)

liver cyst ( J:47035 , J:158354 )

• all have 1-10 liver cysts (J:47035)

• at 9-12 months of age, multiple fluid-filled cysts of different size and shapes are noted in the liver parenchyma (J:158354)

• hepatic cysts posses microvilli and have well-developed cellular junctions (J:158354)

• epithelial cells lining liver cysts stain positively for CK-19, suggesting that hepatic cysts arise from cholangiocytes (J:158354)

• most hepatic cysts are lined by a single layer of cholangiocytes while ~10% of liver cysts are multilayered (J:158354)

• total liver cystic volume increases from ~15.84% of total liver parenchyma at 5-8 months to ~23.26% at 9-12 months of age, as assessed by micro-CT scanning (J:158354)

enlarged liver ( J:158354 )

• mutant livers are significantly enlarged with multiple macroscopically visible cysts, often occupying most of the abdominal cavity

increased liver weight ( J:158354 )

• at 5-8 months of age, mutant liver weights represent ~6% of total body weight relative to ~4.7% in wild-type controls

• by 9-12 months of age, mutant liver weights account for ~8% of total body weight, with no significant differences between male and female mice

liver fibrosis ( J:158354 )

• at 5-8 months of age, mild fibrotic deposits are observed around liver cysts, occupying ~2.71% of total liver parenchyma relative to ~0.92% in wild-type controls

• no changes in hepatic fibrosis are found during disease progression

homeostasis/metabolism

increased blood urea nitrogen level ( J:59314 , J:220561 )

• develop azotemia/uremia (J:59314)

• blood urea nitrogen levels are increased to the same extent as in single Pkd1^tm1.1Pcha homozygotes (J:220561)

endocrine/exocrine glands

abnormal cholangiocyte morphology ( J:158354 )

• cystic cholangiocytes lining intrahepatic bile ducts are enlarged with a thickened basement membrane and a significantly larger width (i.e. distance between two cell junctions) relative to wild-type cholangiocytes

• most cystic cholangiocytes are squamous in appearance

abnormal cholangiocyte primary cilium morphology ( J:158354 )

• cystic cholangiocyte cilia are ~2-fold shorter than wild-type

• ~25% of primary cilia in cystic cholangiocytes appear malformed (e.g. bulbs at the ciliary tip)

bile duct proliferation ( J:47035 , J:158354 )

• 3 of 6 have bile duct proliferation (J:47035)

• at 5-8 months of age, ~18.77% nuclei of cystic cholangiocytes are PCNA-positive relative to ~1.12% in wild-type cholangiocytes; however, the % of PCNA-positive nuclei does not change significantly with age (~20.26% at 9-12 months) (J:158354)

pancreas cyst ( J:59314 )

• 50% of mutants over 3 months of age have visible cysts

cellular

abnormal cholangiocyte primary cilium morphology ( J:158354 )

• cystic cholangiocyte cilia are ~2-fold shorter than wild-type

• ~25% of primary cilia in cystic cholangiocytes appear malformed (e.g. bulbs at the ciliary tip)

increased kidney apoptosis ( J:158354 )

• in cystic renal epithelia cells, apoptotic indices are gradually increased from ~13.55% at 5-8 months of age to ~21.02% at 9-12-months of age, unlike in wild-type cells (~2.86%)

increased cholangiocyte apoptosis ( J:158354 )

• at 5-8 months of age, apoptotic indices in cystic cholangiocytes are increased to ~3.41% relative to ~0.56% in wild-type cholangiocytes, but do not change significantly with age (~3.86% at 9-12 months)

increased kidney cell proliferation ( J:158354 )

• at 5-8 months of age, ~2.86% nuclei of cystic renal epithelial cells are PCNA-positive relative to ~0.85% in wild-type cells; like in hepatic cysts, the % of PCNA-positive nuclei does not change significantly (~2.55%) with age

growth/size/body

pancreas cyst ( J:59314 )

• 50% of mutants over 3 months of age have visible cysts

polycystic kidney ( J:47035 , J:59314 , J:158354 , J:220561 )

• all have bilateral renal cysts (J:47035)

• exhibit renal cyst formation by 6-10 weeks of age that progresses to cystic replacement of normal renal parenchyma later in life (J:59314)

• numerous macroscopically visible cysts are scattered on the kidney surface at an early disease stage (J:158354)

• total renal cystic volume decreases from ~ 40.67% of total kidney parenchyma at 5-8 months to ~31.04% at 9-12 months of age (J:158354)

• primary cilia in cystic renal epithelial cells remain normal despite a tendency to be shorter (J:158354)

• no significant fibrosis is noted around renal cysts in either age group (J:158354)

• mice show a similar level of polycystic kidney disease as single Pkd1^tm1.1Pcha homozygotes (J:220561)

liver cyst ( J:47035 , J:158354 )

• all have 1-10 liver cysts (J:47035)

• at 9-12 months of age, multiple fluid-filled cysts of different size and shapes are noted in the liver parenchyma (J:158354)

• hepatic cysts posses microvilli and have well-developed cellular junctions (J:158354)

• epithelial cells lining liver cysts stain positively for CK-19, suggesting that hepatic cysts arise from cholangiocytes (J:158354)

• most hepatic cysts are lined by a single layer of cholangiocytes while ~10% of liver cysts are multilayered (J:158354)

• total liver cystic volume increases from ~15.84% of total liver parenchyma at 5-8 months to ~23.26% at 9-12 months of age, as assessed by micro-CT scanning (J:158354)

enlarged kidney ( J:158354 )

• mutant kidneys are enlarged with numerous macroscopically visible cysts

increased kidney weight ( J:158354 , J:220561 )

• at 5-8 months of age, mutant kidney weights represent ~2% of total body weight (J:158354)

• by 9-12 months of age, mutant kidney weights account for ~2.6% of total body weight (J:158354)

• kidney weight to body weight ratio is increased to the same extent as in single Pkd1^tm1.1Pcha homozygotes (J:220561)

enlarged liver ( J:158354 )

• mutant livers are significantly enlarged with multiple macroscopically visible cysts, often occupying most of the abdominal cavity

increased liver weight ( J:158354 )

• at 5-8 months of age, mutant liver weights represent ~6% of total body weight relative to ~4.7% in wild-type controls

• by 9-12 months of age, mutant liver weights account for ~8% of total body weight, with no significant differences between male and female mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
polycystic kidney disease 2		DOID:0110859	OMIM:613095	J:47035