Phenotypes associated with this allele

• Allele Symbol: Mad2l1bp^tm1.1Itl
• Allele Name: targeted mutation 1.1, Ingenious Trageting Laboratory
• Allele ID: MGI:6356607
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Mad2l1bp^tm1.1Itl/Mad2l1bp^tm1.1Itl Speer6-ps1^Tg(Alb-cre)21Mgn/Speer6-ps1^+	involves: 129S6/SvEvTac * C57BL/6 * C57BL/6J * C57BL/6NTac	MGI:6791347
cn2	Bub1b^tm1Jvd/Bub1b^tm1Jvd Mad2l1bp^tm1.1Itl/Mad2l1bp^tm1.1Itl Speer6-ps1^Tg(Alb-cre)21Mgn/Speer6-ps1^+	involves: 129S6/SvEvTac * C57BL/6 * FVB	MGI:6791353

Genotype
MGI:6791347

cn1

• Allelic Composition: Mad2l1bp^tm1.1Itl/Mad2l1bp^tm1.1Itl; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6 * C57BL/6J * C57BL/6NTac

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

mortality/aging

mortality/aging ( J:234643 )

N • mice are born in the expected Mendelian ratio and survive to adulthood, unlike Mad2l1bp^tm1.2Itl homozygotes

homeostasis/metabolism

hyperglycemia ( J:234643 )

• at 2 months of age, mice show hyperglycemia in the fed state

• surprisingly, blood glucose levels become normal by 6 months of age

• adeno-associated virus (AAV)-mediated expression of MAD2L1BP (but not of GFP) in the liver rescues the hyperglycemia phenotype

increased circulating insulin level ( J:234643 )

• at 2 months of age, mice show hyperinsulinemia in the fed state that is less severe than that in Insr^tm1Khn/Insr^tm1Khn Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺ mice

increased circulating triglyceride level ( J:234643 )

• at 2 months of age, serum triglyceride levels are moderately increased

impaired glucose tolerance ( J:234643 )

• at 2 months of age, male mice develop glucose intolerance that is less severe than that in Insr^tm1Khn/Insr^tm1Khn Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺ mice

• AAV-mediated expression of MAD2L1BP (but not of GFP) in the liver rescues the glucose intolerance phenotype

decreased liver glycogen level ( J:234643 )

• at E18.5, liver glycogen levels are decreased but to a much lesser extent than in Mad2l1bp^tm1.2Itl homozygotes, thus enabling survival

• at 2 months of age, liver glycogen levels are reduced but to a lesser extent than in Insr^tm1Khn/Insr^tm1Khn Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺ mice

• however, no liver developmental defects are noted at E18.5 or at 2 months of age

insulin resistance ( J:234643 )

• at 2 months of age, male mice develop insulin intolerance that is less severe than that in Insr^tm1Khn/Insr^tm1Khn Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺ mice

• AAV-mediated expression of MAD2L1BP (but not of GFP) in the liver rescues the insulin intolerance phenotype

decreased liver triglyceride level ( J:234643 )

• at 2 months of age, hepatic triglyceride levels are decreased by about 50%

abnormal enzyme/coenzyme activity ( J:234643 )

• insulin treatment fails to stimulate glycogen synthase activity (GS) in hepatocytes, unlike in wild-type hepatocytes

liver/biliary system

decreased liver glycogen level ( J:234643 )

• at E18.5, liver glycogen levels are decreased but to a much lesser extent than in Mad2l1bp^tm1.2Itl homozygotes, thus enabling survival

• at 2 months of age, liver glycogen levels are reduced but to a lesser extent than in Insr^tm1Khn/Insr^tm1Khn Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺ mice

• however, no liver developmental defects are noted at E18.5 or at 2 months of age

decreased liver triglyceride level ( J:234643 )

• at 2 months of age, hepatic triglyceride levels are decreased by about 50%

abnormal liver physiology ( J:234643 )

• insulin receptor (IR) autophosphorylation and activating phosphorylation of AKT (pT308) are significantly reduced whereas inhibitory phosphorylation of GSK3 (pS9) is modestly reduced in whole-liver lysates from insulin-treated mice

• AAV-mediated expression of MAD2L1BP (but not of GFP) in the liver rescues the insulin signaling defects

abnormal hepatocyte physiology ( J:234643 )

• insulin-dependent glycogen synthase (GS) activation is abolished in hepatocytes

• freshly isolated primary hepatocytes display weakened and delayed IR autophosphorylation and AKT pT308 at multiple time points and over a wide range of insulin concentrations

cellular

aneuploidy ( J:234643 )

• only 10% (1 out of 10) live hepatocytes is aneuploid relative to none (0 of 15) wild-type hepatocytes

• AAV-mediated expression of MAD2L1BP does not eliminate aneuploidy: 5% (2 of 39) hepatocytes are aneuploid vs only 2.5% (1 of 40) hepatocytes in the AAV-GFP control group

abnormal endocytosis ( J:234643 )

• hepatocytes show defective insulin endocytosis as a result of a reduced level of functional IR at the plasma membrane, due to premature internalization of IR prior to insulin stimulation

Genotype
MGI:6791353

cn2

• Allelic Composition: Bub1b^tm1Jvd/Bub1b^tm1Jvd; Mad2l1bp^tm1.1Itl/Mad2l1bp^tm1.1Itl; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6 * FVB

mortality/aging

preweaning lethality, incomplete penetrance ( J:234643 )

• mice are obtained at a slightly lower than the expected number (10 versus 14.5) based on the Mendelian ratio; time of lethality is not specified

growth/size/body

decreased body weight ( J:234643 )

• mice attain ~40% of normal weight at 3 weeks of age

postnatal growth retardation ( J:234643 )

• mice appear normal at birth but fail to thrive, similar to Bub1b^tm1Jvd homozygotes

homeostasis/metabolism

hypoglycemia ( J:234643 )

• mice exhibit hypoglycemia in the fed state, similar to Bub1b^tm1Jvd homozygotes and opposite to Mad2l1bp^tm1.1Itl/Mad2l1bp^tm1.1Itl Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺ mice

improved glucose tolerance ( J:234643 )

• mice exhibit increased glucose tolerance, similar to Bub1b^tm1Jvd homozygotes and opposite to Mad2l1bp^tm1.1Itl/Mad2l1bp^tm1.1Itl Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺ mice

increased insulin sensitivity ( J:234643 )

• mice exhibit increased insulin sensitivity, similar to Bub1b^tm1Jvd homozygotes and opposite to Mad2l1bp^tm1.1Itl/Mad2l1bp^tm1.1Itl Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺ mice

liver/biliary system

abnormal hepatocyte morphology ( J:234643 )

• at 2 months of age, the cell and nuclear sizes of hepatocytes in male mice are larger than those in single knockout mice

increased hepatocyte karyomegaly ( J:234643 )

cellular

polyploidy ( J:234643 )

• mice exhibit an increased percentage of hepatocytes with 8N or greater DNA content, indicating a striking ploidy change

increased hepatocyte karyomegaly ( J:234643 )