Phenotypes associated with this allele

• Allele Symbol: Pcca^tm1Tmiy
• Allele Name: targeted mutation 1, Toru Miyazaki
• Allele ID: MGI:2180816
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Pcca^tm1Tmiy/Pcca^tm1Tmiy	involves: 129P2/OlaHsd * C57BL/6	MGI:3052741
cx2	Pcca^tm1Tmiy/Pcca^tm1Tmiy Tg(CAG-PCCA*A138T,-EGFP)#Miab/0	involves: 129P2/OlaHsd * FVB/N	MGI:6404457

Genotype
MGI:3052741

hm1

• Allelic Composition: Pcca^tm1Tmiy/Pcca^tm1Tmiy
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

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

mortality/aging

postnatal lethality, complete penetrance ( J:71660 )

• die 24-36 hours after birth due to accelerated ketoacidosis

behavior/neurological

absent gastric milk in neonates ( J:71660 )

• no milk intake 10-12 hours after birth

• little or no gastric milk 24 hours after birth

abnormal stationary movement ( J:71660 )

homeostasis/metabolism

dehydration ( J:71660 )

decreased liver glycogen level ( J:71660 )

• disappearance of glycogen in liver between E18.5 and 24 hours after birth

ketoaciduria ( J:71660 )

• ketonuria detected 10 hours after birth

• accumulation of propionyl-CoA

liver/biliary system

decreased liver glycogen level ( J:71660 )

• disappearance of glycogen in liver between E18.5 and 24 hours after birth

hepatic steatosis ( J:71660 )

• significant fat deposition detected between E18.5 and 24 hours after birth

renal/urinary system

ketoaciduria ( J:71660 )

• ketonuria detected 10 hours after birth

• accumulation of propionyl-CoA

dilated kidney collecting duct ( J:71660 )

• enlarged with hyaline droplet casts

renal cast ( J:71660 )

• collecting ducts are enlarged with marked incorporation of hyaline droplet casts

abnormal urination ( J:71660 )

• poor urination

integument

dry skin ( J:71660 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
propionic acidemia		DOID:14701	OMIM:606054	J:71660

Genotype
MGI:6404457

cx2

• Allelic Composition: Pcca^tm1Tmiy/Pcca^tm1Tmiy; Tg(CAG-PCCA*A138T,-EGFP)#Miab/0
• Genetic Background: involves: 129P2/OlaHsd * FVB/N

cellular

oxidative stress ( J:282292 )

♂ • cardiomyocytes show increased ROS levels

maternal effect ( J:286218 )

• pups from matings of homozygous Pcca^tm1Tmiy mice harboring the Tg(CAG-PCCA*A138T,-EGFP)#Maba transgene are much smaller than pups from matings of heterozygous Pcca^tm1Tmiy mice harboring the Tg(CAG-PCCA*A138T,-EGFP)#Maba transgene; phenotypic data reported below is for mice produced from Pcca^tmTmiy/Pcca^tm1Tmiy Tg(CAG-PCCA*A138T,-EGFP)#Maba/0 parents

mortality/aging

decreased survivor rate ( J:286218 )

• marginally decreased survival over 3 months after birth, with more than 75% survival beyond 90 days

growth/size/body

enlarged heart ( J:286218 )

• heart mass is increased in 8 month old mice

decreased body size ( J:286218 )

• pups are smaller

postnatal growth retardation ( J:286218 )

• pups show delayed growth throughout neonatal development

homeostasis/metabolism

abnormal circulating carnitine level ( J:286218 )

• increase in levels of propionylcarnitine/acetylcarnitine (C3/C2) ratio and methyl citrate beginning at 4 weeks of age, with an 18-fold increase in both on average

• 10 week old mice treated with adenoviral vectors expressing codon-optimized human PCCA show increases in growth and partial correction of C3/C2 and methyl citrate levels, however the effects are transient

• mice treated with AAV8 vectors expressing codon-optimized human PCCA show a rapid drop in C3/C2 and methyl citrate that is maintained for at least 13 weeks; treated 5 week old mice show a stronger effect than 10 week old mice

increased circulating alanine level ( J:286218 )

increased circulating glycine level ( J:286218 )

increased lysine level ( J:286218 )

increased circulating ammonia level ( J:286218 )

• plasma ammonia levels are elevated in 8 month old mice

abnormal enzyme/coenzyme activity ( J:286218 )

• livers show 2.2% of wild-type propionyl-CoA carboxylase activity

cardiovascular system

enlarged heart ( J:286218 )

• heart mass is increased in 8 month old mice

decreased cardiac muscle contractility ( J:282292 )

♂ • 58% of mice show depressed cardiac function due to a decrease in ejection fraction

♂ • failure of hearts to complete the systolic cycle, with an increase in left ventricular volume at the end of systole indicating impaired cardiac contractility

♂ • however, no evidence of cardiac hypertrophy development and cardiomyocyte surface and cell capacitance are normal

ventricular premature beat ( J:282292 )

♂ • 40% of mice show spontaneous premature ventricular beats

abnormal myocardial fiber physiology ( J:282292 )

♂ • cardiomyocytes show depressed cell shortening and slower cell contraction velocity

♂ • systolic calcium release in field-stimulated isolated cardiomyocytes is impaired, with lower amplitude of intracellular calcium transients elicited at 2 or 4 Hz

♂ • cardiomyocytes show irregular diastolic calcium release, showing an increase in cytosolic calcium levels at rest

♂ • the frequency of calcium sparks normalized to sarcoplasmic reticulum calcium load is higher in cardiomyocytes

♂ • the percentage of cardiomyocytes presenting proarrhythmogenic calcium release is higher than in controls

♂ • cardiomyocytes show impaired sarcoplasmic reticulum calcium load

decreased calcium uptake by cardiac muscle ( J:282292 )

♂ • sarcoplasmic reticulum (SR)-calcium uptake is impaired in cardiomyocytes, with slower decay time of intracellular transients and lower values of Tau/peak intracellular transients ratio

muscle

decreased cardiac muscle contractility ( J:282292 )

♂ • 58% of mice show depressed cardiac function due to a decrease in ejection fraction

♂ • failure of hearts to complete the systolic cycle, with an increase in left ventricular volume at the end of systole indicating impaired cardiac contractility

♂ • however, no evidence of cardiac hypertrophy development and cardiomyocyte surface and cell capacitance are normal

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
propionic acidemia		DOID:14701	OMIM:606054	J:282292 , J:286218