Phenotypes associated with this allele

• Allele Symbol: Mmut^tm1Cpv
• Allele Name: targeted mutation 1, Charles P Venditti
• Allele ID: MGI:3840300
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Mmut^tm1Cpv/Mmut^tm1Cpv	involves: 129S/SvEv * C57BL/6	MGI:3840341
hm2	Mmut^tm1Cpv/Mmut^tm1Cpv	involves: 129S/SvEv * C57BL/6 * FVB/N	MGI:3840342
hm3	Mmut^tm1Cpv/Mmut^tm1Cpv	Not Specified	MGI:3840340
cx4	Mmut^tm1Cpv/Mmut^tm1Cpv Tg(Alb-Mut)#Cpv/0	involves: C57BL/6	MGI:5527455

Genotype
MGI:3840341

hm1

• Allelic Composition: Mmut^tm1Cpv/Mmut^tm1Cpv
• Genetic Background: involves: 129S/SvEv * C57BL/6

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

mortality/aging

neonatal lethality, incomplete penetrance ( J:147313 )

• Background Sensitivity: mice die shortly after birth unlike on a mixed 129S/SvEv, C57BL/6, and FVB/N background where a few mice survive weaning

Genotype
MGI:3840342

hm2

• Allelic Composition: Mmut^tm1Cpv/Mmut^tm1Cpv
• Genetic Background: involves: 129S/SvEv * C57BL/6 * FVB/N

mortality/aging

decreased survivor rate ( J:147313 )

• few mice survive post-weaning

postnatal lethality, incomplete penetrance ( J:147313 )

• Background Sensitivity: a few mice survive post-weaning whereas no mice survive weaning on a congenic C57BL/6 background

homeostasis/metabolism

abnormal blood homeostasis ( J:147313 )

• levels of plasma methylmalonic acid are higher than in wild-type mice

• mice exhibit a decrease in free carnitine, valine, isoleucine, and orinthine, and elevated propionylcarnitine and alanine compared to in wild-type mice

abnormal circulating amino acid level ( J:147313 )

• mice exhibit a decrease in free carnitine, valine, isoleucine, and orinthine, and elevated propionylcarnitine and alanine compared to in wild-type mice

organic aciduria ( J:147313 )

• in one ill mouse, the urine organic acid content is increased compared to in wild-type mice

endocrine/exocrine glands

abnormal pancreas morphology ( J:147313 )

• in older mice, pancreatic cells show megamitochondria compared to in wild-type cells

abnormal exocrine pancreas morphology ( J:147313 )

• in older mice, exocrine pancreatic cells exhibit fewer zymogen granules than in wild-type cells

abnormal pancreatic beta cell morphology ( J:147313 )

• in older mice, beta cells have fewer insulin granules than in wild-type cells

renal/urinary system

organic aciduria ( J:147313 )

• in one ill mouse, the urine organic acid content is increased compared to in wild-type mice

tubulointerstitial nephritis ( J:147313 )

• tubulointerstitial inflammation in older mice

abnormal proximal convoluted tubule morphology ( J:147313 )

• beginning on day 7, cells within the proximal convoluted tubules exhibit megamitochondria with underdeveloped cristae and peculiar lamellations unlike in wild-type cells

liver/biliary system

abnormal hepatocyte mitochondrial morphology ( J:147313 )

• hepatocyte mitochondrial become enlarged and exhibit dysmorphic cristae, intramitochondrial lamellar inclusion body formation, and a less electron-dense matrix compared to in wild-type cells

hepatic steatosis ( J:147313 )

• the number and size of lipid droplets in hepatocytes is increased compared to in wild-type mice

cellular

abnormal hepatocyte mitochondrial morphology ( J:147313 )

• hepatocyte mitochondrial become enlarged and exhibit dysmorphic cristae, intramitochondrial lamellar inclusion body formation, and a less electron-dense matrix compared to in wild-type cells

abnormal tricarboxylic acid cycle ( J:147313 )

• citrate synthase activity is decreased in hepatocytes compared to in wild-type cells

abnormal respiratory electron transport chain ( J:147313 )

• complex I + III and complex II + III activities are decreased in hepatocytes compared to in wild-type cells

• COX activity is decreased more than 50% in hepatocytes compared to in wild-type cells

• however, mitochondrial function in skeletal muscle and whole kidney samples is normal

growth/size/body

decreased body weight ( J:147313 )

• mice weigh 66%, 67%, 69%, and 51% of wild-type at 6, 14, 18, and 230 days, respectively

postnatal growth retardation ( J:147313 )

• early and significant

digestive/alimentary system

abnormal exocrine pancreas morphology ( J:147313 )

• in older mice, exocrine pancreatic cells exhibit fewer zymogen granules than in wild-type cells

immune system

tubulointerstitial nephritis ( J:147313 )

• tubulointerstitial inflammation in older mice

Genotype
MGI:3840340

hm3

• Allelic Composition: Mmut^tm1Cpv/Mmut^tm1Cpv
• Genetic Background: Not Specified

mortality/aging

postnatal lethality, complete penetrance ( J:147338 )

• mice die between 24 and 36 hours after birth with respiratory distress

homeostasis/metabolism

abnormal blood homeostasis ( J:147338 )

• at E16.5 and in newborn mice, levels of plasma methylmalonic acid are higher than in wild-type mice

acidemia ( J:147338 )

• at 8 to 12 hours of age, mice exhibit methylmalonic acidemia unlike wild-type mice

dehydration ( J:147338 )

• 24 hours after birth, mice exhibit a reduction in the stomach milk spot and dehydration unlike wild-type mice

aciduria ( J:147338 )

• at 8 to 12 hours of age, mice exhibit methylmalonic aciduria unlike wild-type mice

respiratory system

lung hemorrhage ( J:147338 )

• in 2 of 8 mice

respiratory distress ( J:147338 )

• 24 and 36 hours after birth

liver/biliary system

abnormal liver morphology ( J:147338 )

• at 24 to 36 hours after birth, mice exhibit non-necrotic lipidotic changes in the liver unlike in wild-type mice

nervous system

abnormal brain morphology ( J:147338 )

• the brain appears compressed against the dura mater unlike in wild-type mice

renal/urinary system

aciduria ( J:147338 )

• at 8 to 12 hours of age, mice exhibit methylmalonic aciduria unlike wild-type mice

cardiovascular system

lung hemorrhage ( J:147338 )

• in 2 of 8 mice

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:147338

Genotype
MGI:5527455

cx4

• Allelic Composition: Mmut^tm1Cpv/Mmut^tm1Cpv; Tg(Alb-Mut)#Cpv/0
• Genetic Background: involves: C57BL/6

Enlarged mitochondria with whorl-like cristae in Mmut^tm1Cpv/Mmut^tm1Cpv Tg(Alb-Mut)#Cpv/0 mice fed a high-protein diet

mortality/aging

premature death ( J:200689 )

• mice fed a high-protein diet at the age of 2-3 months for 2 months show a 52% survival rate, with males more severely affected

• males fed a high-protein diet rarely survive beyond 2 months of age

• treatment of mice fed a high-protein diet with the antioxidant, ubiquinone, improves survival

growth/size/body

weight loss ( J:200689 )

♀ • females fed a high-protein (casein) diet exhibit rapid weight loss of 14% within the first month and fail to regain weight

♀ • treatment of mice fed a high-protein diet with the antioxidant, ubiquinone, decreases weight loss

homeostasis/metabolism

increased circulating creatinine level ( J:200689 )

♂ • males, but not females, fed a high-protein diet for 2 months exhibit an increase in serum creatinine

decreased circulating bicarbonate level ( J:200689 )

♂ • males fed a regular diet exhibit lower plasma bicarbonate levels

increased circulating lipocalin 2 level ( J:200689 )

• mice on a high-protein diet for 2 months exhibit increased plasma Lcn2 (lipocalin-2) levels, a biomarker for renal dysfunction and oxidative stress

increased circulating chloride level ( J:200689 )

♂ • males fed a regular diet exhibit higher plasma chloride concentrations

metabolic acidosis ( J:200689 )

♂ • males fed a regular diet exhibit lower plasma bicarbonate and higher plasma chloride levels indicating chronic hyperchloremic metabolic acidosis, however urinary ammonium excretion is not increased

increased circulating methylmalonic acid level ( J:200689 )

• elevation in plasma methylmalonic acid levels

• females fed a high-protein diet exhibit increased plasma methylmalonic acid levels

renal/urinary system

tubulointerstitial nephritis ( J:200689 )

♀ • females fed a high-protein diet for 6 months develop severe multifocal tubulointerstitial nephritis, with a granular kidney cortex appearance, and fine microvesicular cytoplasmic changes in the convoluted proximal segment tubules

♀ • however, glomeruli appear normal and podocyte foot processes are not effaced in mice fed a high-protein diet for 6 months

abnormal kidney morphology ( J:200689 )

♀ • females fed a high-protein diet for 6 months exhibit a large number of mitochondria in the kidneys with electron-dense matrix and abnormal cristae in the proximal tubules

♀ • however, kidneys appear histologically normal after 2 months on a high-protein diet

abnormal renal tubule morphology ( J:200689 )

• multiple matrix granules/deposits in the renal tubular cytosol

decreased renal glomerular filtration rate ( J:200689 )

• mice fed a high-protein diet for 2 months show a reduction in glomerular filtration rate compared to heterozygous controls or mutants on a regular diet

• single-nephron glomerular filtration rate is lower in males fed a regular diet

• whole-body glomerular filtration rate in mice fed a regular diet is not decreased until 9-12 months of age

• treatment of mice fed a high-protein diet with the antioxidant, ubiquinone, improves glomerular filtration rate

abnormal renal reabsorption ( J:200689 )

• diminution of the proximal tubule fluid reabsorption rate in males fed a regular diet, however males also show a lower fractional fluid reabsorption, indicating reduced reabsorptive capacity of the proximal tubule independent of glomerular filtration rate

cellular

abnormal mitochondrial crista morphology ( J:200689 )

♀ • females fed a high-protein diet for 6 months exhibit a large number of mitochondria in the kidneys with electron-dense matrix and abnormal cristae in the proximal tubules

abnormal mitochondrial matrix morphology ( J:200689 )

♀ • females fed a high-protein diet for 6 months exhibit a large number of mitochondria in the kidneys with electron-dense matrix and abnormal cristae in the proximal tubules

oxidative stress ( J:200689 )

• mice on a high-protein diet for 2 months exhibit increased plasma Lcn2 (lipocalin-2) levels, a biomarker for renal dysfunction and oxidative stress

immune system

tubulointerstitial nephritis ( J:200689 )

♀ • females fed a high-protein diet for 6 months develop severe multifocal tubulointerstitial nephritis, with a granular kidney cortex appearance, and fine microvesicular cytoplasmic changes in the convoluted proximal segment tubules

♀ • however, glomeruli appear normal and podocyte foot processes are not effaced in mice fed a high-protein diet for 6 months

nervous system

abnormal brain morphology ( J:200689 )

♀ • females fed a high-protein diet for 2 months exhibit higher methylmalonic acid concentrations in the brain compared to mice fed regular chow

liver/biliary system

liver/biliary system phenotype ( J:200689 )

♀N • liver appears normal in mice fed a high-protein diet

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:200689