Phenotypes associated with this allele

• Allele Symbol: Mmut^tm1Pai
• Allele Name: targeted mutation 1, Panayiotis A Ioannou
• Allele ID: MGI:3026839
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Mmut^tm1Pai/Mmut^tm1Pai	involves: 129S1/Sv * C57BL/6	MGI:3026845
ht2	Mmut^tm1Pai/Mmut^tm1.1Mrb	involves: 129S1/Sv * C57BL/6	MGI:6157365
cx3	Mmut^tm1Pai/Mmut^tm1Pai Tg(MUT*R403X)#Hlps/0	involves: 129S1/Sv * C57BL/6	MGI:5464284
cx4	Mmut^tm1Pai/Mmut^tm1Pai Tg(MUT)AHlps/0 Tg(MUT*R403X)#Hlps/0	involves: 129S1/Sv * C57BL/6	MGI:5464285

Genotype
MGI:3026845

hm1

• Allelic Composition: Mmut^tm1Pai/Mmut^tm1Pai
• Genetic Background: involves: 129S1/Sv * C57BL/6

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

mortality/aging

neonatal lethality, complete penetrance ( J:87081 )

• although homozygotes are born normally and exhibit normal activity and suckling shortly after birth, none of them survive past 24 hrs of age

behavior/neurological

absent gastric milk in neonates ( J:87081 )

• homozygotes display reduced/absent milk spots by 15-18 hrs of age

• however, large gastric milk spots are observed shortly after birth

abnormal suckling behavior ( J:87081 )

• homozygotes stop suckling by 15-18 hrs of age

decreased locomotor activity ( J:87081 )

• although homozygotes are initially vigorous, they show a gradual decrease in activity by 15-18 hrs of age

homeostasis/metabolism

increased circulating carnitine level ( J:87081 )

• newborn homozygotes show a ~6-fold increase in mean circulating propionylcarnitine (C3) levels relative to wild-type and heterozygous controls

• ratios of propionylcarnitine to free carnitine (C3:C0) and to acetylcarnitine (C3:C2) are ~7-fold higher than in controls

• blood levels of free carnitine (CO) and acetylcarnitine (C2) remain normal

methylmalonic aciduria ( J:87081 )

• urinary levels of methylmalonic and methylcitric acids are grossly increased, as shown by gas chromatography-mass spectrometry

• urinary levels of methylmalonic acid are grossly elevated shortly after birth, with progressive accumulation at various time points prior to death

• however, no evidence of ketonuria is observed

renal/urinary system

methylmalonic aciduria ( J:87081 )

• urinary levels of methylmalonic and methylcitric acids are grossly increased, as shown by gas chromatography-mass spectrometry

• urinary levels of methylmalonic acid are grossly elevated shortly after birth, with progressive accumulation at various time points prior to death

• however, no evidence of ketonuria is observed

respiratory system

respiratory distress ( J:87081 )

• homozygotes exhibit intermittent gasping prior to death

liver/biliary system

abnormal liver parenchyma morphology ( J:87081 )

• at 20 hrs (but not at 12 hrs) of age, homozygotes display a moderate fatty change in liver parenchyma

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency		DOID:0060740	OMIM:251000	J:87081

Genotype
MGI:6157365

ht2

• Allelic Composition: Mmut^tm1Pai/Mmut^tm1.1Mrb
• Genetic Background: involves: 129S1/Sv * C57BL/6

growth/size/body

decreased body weight ( J:237040 )

• females show a 30% difference in body weight from wild-type mice at about 1 year of age

• however, food intake remains constant

weight loss ( J:237040 )

• mice fed a high protein (HP) diet or a precursor-enriched (PE) diet comprised of increased levels of precursor amino acids of propionate pathway metabolites exhibit a rapid weight loss, with more pronounced weight loss on the PE diet

• mice fed a high protein diet and treated with cobalamin show a slight protective effect, with a delay in weight loss, although increases in metabolite levels still occur

postnatal growth retardation ( J:237040 )

• mice show significant growth retardation after the age of about 100 days in females and about 150 days in males

homeostasis/metabolism

increased circulating carnitine level ( J:237040 )

• propionylcarnitine (normalized to acetylcarnitine) in blood is constantly elevated

• mice fed a HP or PE diet show further elevations in propionylcarnitine levels

increased circulating glycine level ( J:237040 )

• mice exhibit elevated glycine levels in blood

• however, other amino acid levels are mostly unchanged

increased circulating ammonia level ( J:237040 )

• mice fed a HP or PE diet show increased ammonia levels, indicative of metabolic crisis induction

• however, mice fed a regular chow diet exhibit normal ammonia levels

increased blood urea nitrogen level ( J:237040 )

• increase in plasma urea

increased urine chloride ion level ( J:237040 )

increased urine potassium level ( J:237040 )

increased urine sodium level ( J:237040 )

abnormal fatty acids level ( J:237040 )

• mice exhibit increased levels of odd chain fatty acids in plasma, including the 17-carbon chain length fatty acid

• however, levels of even chain fatty acids are normal

abnormal sphingolipid level ( J:237040 )

• mice exhibit an elevation of odd chain length sphingoid bases in plasma and tissues

• however, levels of even chain sphingoid bases remains normal

acidosis ( J:237040 )

• methylmalonic acid levels are elevated in tissues and dried blood

• however, mice show normal ammonia levels

• mice fed a HP or PE diet show further elevations in methylmalonic acid levels

increased lipocalin 2 level ( J:237040 )

• mice show an up-regulation in Lcn2 (lipocalin-2) at the mRNA and protein level in brain tissue, as well as increased protein levels of lipocalin-2 in kidney tissue

increased urine calcium level ( J:237040 )

increased urine magnesium level ( J:237040 )

methylmalonic aciduria ( J:237040 )

• methylmalonic acid levels in urine are constantly elevated

• mice fed a HP or PE diet show further elevations in methylmalonic acid levels

nervous system

abnormal brain morphology ( J:237040 )

• mice show increased levels of the biomarker lipocalin-2 in the brain

increased brain weight ( J:237040 )

• increase in brain weight at 1 month and 1 year of age

• however, brain histology is normal in the basal ganglia

• mice fed a HP or PE diet show increased brain weight (normalized to body weight)

• mice fed a high protein diet and treated with cobalamin show a slight protective effect, with no increase in brain weight, although increases in metabolite levels still occur

renal/urinary system

increased urine chloride ion level ( J:237040 )

increased urine potassium level ( J:237040 )

increased urine sodium level ( J:237040 )

increased urine calcium level ( J:237040 )

increased urine magnesium level ( J:237040 )

methylmalonic aciduria ( J:237040 )

• methylmalonic acid levels in urine are constantly elevated

• mice fed a HP or PE diet show further elevations in methylmalonic acid levels

abnormal kidney morphology ( J:237040 )

• mice show increased levels of the biomarker lipocalin-2 in kidney tissue indicating kidney damage

abnormal kidney physiology ( J:237040 )

• mice exhibit disturbed excretion of several electrolytes in urine, indicating renal tubular dysfunction

oliguria ( J:237040 )

• mice produce less urine during adulthood than controls, when normalized for body weight

• however, water intake is not different from controls

mortality/aging

mortality/aging ( J:237040 )

N • mice exhibit a normal life span

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency		DOID:0060740	OMIM:251000	J:237040

Genotype
MGI:5464284

cx3

• Allelic Composition: Mmut^tm1Pai/Mmut^tm1Pai; Tg(MUT*R403X)#Hlps/0
• Genetic Background: involves: 129S1/Sv * C57BL/6

mortality/aging

neonatal lethality, complete penetrance ( J:191879 )

homeostasis/metabolism

abnormal homeostasis ( J:191879 )

• high methylmalonic acid in the liver, brain and kidney prior to birth with no increase after birth

increased circulating carnitine level ( J:191879 )

• increased C3 propionylcarnitine in the urine and blood 1 day prior to birth, at birth and at 16 hours

acidosis ( J:191879 )

• high methylmalonic acid in the blood

methylmalonic aciduria ( J:191879 )

• high methylmalonic acid in the urine

renal/urinary system

methylmalonic aciduria ( J:191879 )

• high methylmalonic acid in the urine

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency		DOID:0060740	OMIM:251000	J:191879

Genotype
MGI:5464285

cx4

• Allelic Composition: Mmut^tm1Pai/Mmut^tm1Pai; Tg(MUT)AHlps/0; Tg(MUT*R403X)#Hlps/0
• Genetic Background: involves: 129S1/Sv * C57BL/6

homeostasis/metabolism

abnormal homeostasis ( J:191879 )

• high methylmalonic acid in the urine, blood, liver, kidney, brain and muscle at 6 weeks

increased circulating carnitine level ( J:191879 )

• increased C3 propionylcarnitine in the urine and blood 1 day prior to birth, at birth and at 16 hours

acidosis ( J:191879 )

• high methylmalonic acid in the blood at 6 weeks, but not as much as in Mut^tm1Pai/Mut^tm1Pai Tg(MUT*R403X)#Hlps mice

methylmalonic aciduria ( J:191879 )

• high methylmalonic acid in the urine at 6 weeks

abnormal metabolism ( J:191879 )

• mice have occasional episodes of sickness (decreased movement, hunched over and ruffled fur) from which they recover within 2 hours of treatment with a liquid mixture of ground up food pellet and baby formula and placement on a heat pad

• however, feeding mice this diet during the first part of life prevents these episodes

growth/size/body

decreased body size ( J:191879 )

• more so in female mice

decreased body weight ( J:191879 )

• more so in female mice

increased kidney weight ( J:191879 )

• at 2 years

increased liver weight ( J:191879 )

• at 2 years

liver/biliary system

increased liver weight ( J:191879 )

• at 2 years

renal/urinary system

increased kidney weight ( J:191879 )

• at 2 years

methylmalonic aciduria ( J:191879 )

• high methylmalonic acid in the urine at 6 weeks

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency		DOID:0060740	OMIM:251000	J:191879