Phenotypes Associated with This Genotype

Genotype
MGI:3836901

• Allelic Composition: Tg(ACTB-Twnk*)DSuom/0
• Genetic Background: involves: FVB/N

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

mortality/aging

mortality/aging ( J:104378 )

N • mice exhibit normal aging and life span

liver/biliary system

abnormal liver morphology ( J:235406 )

• livers show decreased lipid content but no degeneration

cellular

increased cardiac muscle cell glucose uptake ( J:235406 )

• in vivo uptake of glucose, the primary substrate of de novo serine biosynthesis is increased in skeletal muscle and heart

abnormal mitochondrial morphology ( J:104378 , J:235406 )

• deletions in mitochondrial DNA accumulate unlike in wild-type mice (J:104378)

• mice show progressive mutagenesis as multiple mtDNA deletions accumulate in skeletal muscle and heart (J:235406)

increased skeletal muscle cell glucose uptake ( J:235406 )

• in vivo uptake of glucose, the primary substrate of de novo serine biosynthesis is increased in skeletal muscle and heart

abnormal cellular respiration ( J:104378 )

• at 18 months, mice exhibit COX-SDH+, markers of decreased respiratory function and increased proliferation, muscles and brain cells unlike wild-type mice

abnormal DNA methylation ( J:235406 )

• methyl cycle is affected; the precursors to creatine and phosphatidylcholine are increased in muscle; guanidino-acetic acid (GAA) and phosphatidylethanolamine (PE) are increased 1.5- and 1.7-fold, respectively, indicating an aberrant methyl cycle and insufficient methylation capacity for creatine and PC synthesis in skeletal muscle

abnormal DNA repair ( J:104378 )

• deletions in mitochondrial DNA accumulate unlike in wild-type mice

increased mitochondrial fission ( J:104378 )

• at 18 months, mice exhibit COX-SDH+, markers of decreased respiratory function and increased proliferation, muscles and brain cells unlike wild-type mice

muscle

muscle phenotype ( J:104378 )

N • despite mitochondrial defects, mice exhibit normal muscle strength and performance

increased cardiac muscle cell glucose uptake ( J:235406 )

• in vivo uptake of glucose, the primary substrate of de novo serine biosynthesis is increased in skeletal muscle and heart

increased skeletal muscle cell glucose uptake ( J:235406 )

• in vivo uptake of glucose, the primary substrate of de novo serine biosynthesis is increased in skeletal muscle and heart

abnormal muscle morphology ( J:235406 )

• serine and glycine concentrations are increased 1.5- and 2-fold in muscle and heart

• however, no increased serine is seen in the liver or brain

abnormal muscle fiber morphology ( J:104378 )

• at 18 months, muscle fibers exhibit an increase in the number and size of mitochondria compared to in wild-type mice

• severely affected muscle fibers exhibit large mitochondria with concentric cristae and electron-dense inclusions unlike in wild-type mice

• however, total respiration capacity of the muscle is normal

• at 18 months, mice exhibit COX-SDH+, markers of decreased respiratory function and increased proliferation, muscles cells unlike wild-type mice

abnormal skeletal muscle fiber morphology ( J:235406 )

• skeletal muscle harbors cytochrome c oxidase (COX)-deficient muscle fibers

• folinic acid supplementation does not reverse disease pathology, including the COX-negative muscle fibers in 22-month-old mice with advanced disease

myopathy ( J:235406 )

• mice exhibit mitochondrial myopathy

• folinic acid supplementation does not reverse disease pathology (mutant mtDNA amount, COX-negative fibers, and Mthfd2, Fgf21 expression levels) in 22-month-old mice with advanced disease

nervous system

nervous system phenotype ( J:235406 )

N • 24-month-old mice show normal cerebellar and hippocampal CA1 neuronal morphology

abnormal brain morphology ( J:104378 )

• at 18 months, 1% of Purkinje cells in the cerebellum and a few neurons in the olfactory bulbs, substantia nigra, and hypothalamus are COX-SDH+ unlike in wild-type mice that have no COX-SDH+ brain cells

homeostasis/metabolism

abnormal DNA repair ( J:104378 )

• deletions in mitochondrial DNA accumulate unlike in wild-type mice

abnormal homeostasis ( J:235406 )

• increase in glutathione biosynthesis and increase in steady-state levels of gamma-glutamylcysteine in the heart

• muscle shows tissue-specific induction of the mitochondrial folate cycle, purine metabolism, and imbalanced and increased dNTP pools, and modified cytoplasmic one-carbon cycle, trasnsulfuration, and methylation, as well as increased glucose uptake and its utilization for de novo serine and glutathione biosynthesis

increased amino acid betaine level ( J:235406 )

• betaine concentrations are elevated in skeletal muscle and heart suggest the induction of alternate one-carbon sources to replenish the one-carbon pool

increased cystathionine level ( J:235406 )

• increase in steady-state levels of cystathionine in the heart

increased glycine level ( J:235406 )

• glycine concentration is increased 2-fold in muscle and heart

increased serine level ( J:235406 )

• serine concentration is increased 1.5-fold in muscle and heart

increased threonine level ( J:235406 )

• threonine concentrations are elevated in skeletal muscle and heart suggest the induction of alternate one-carbon sources to replenish the one-carbon pool

abnormal amino acid metabolism ( J:235406 )

• 5- to 10-fold increase in gene expression of enzymes of the de novo serine biosynthesis pathway, phosphoglycerate dehydrogenase and phosphoserine aminotransferase

• in vivo uptake of glucose, the primary substrate of de novo serine biosynthesis is increased in skeletal muscle and heart

• different tetrahydrofolate intermediates changes are seen in male muscle; formate, the product of MTHFD1L and substrate for purine synthesis, is 30% that of wild-type level, but tetrahydrofolate (THF) forms show induction, with increased 5-methyl-THF, 5,10-methylene-THF, and THF amounts indicating a steady-state imbalance of folate cycle intermediates with an upregulation of the mitochondrial folate cycle and imbalance of whole cellular folate species

• similar but more subtle changes are seen in female muscle; 5-methyl-THF, which is the cofactor donating one-carbon (1C) units for methylation reactions, and 5,10-methenyl-THF, produced by MTHFD2 and regulating 1C flow toward purine metabolism, are elevated 1.5-fold indicating aberrant cytoplasmic 1C metabolism in skeletal muscle and heart

• in the heart, purine degradation products adenosine, guanosine, inosine, and xanthosine are increased 1.5- to 3-fold and more modest changes of hypoxanthine are seen in skeletal muscle

abnormal enzyme/coenzyme activity ( J:235406 )

• glutathione reductase activity is increased, however no change in glutathione peroxidase activity

• cystathionine gamma-lysase is highly induced in heart and muscle

abnormal nucleotide metabolism ( J:235406 )

• skeletal muscle shows 3-, 2- and 1.3-fold increase in deoxyadenosine triphosphate (dATP), deoxythymidine triphosphate (dTTP) and deoxycytidine triphosphate (dCTP), and deoxyguanosine triphosphate (dGTP), respectively indicating imbalanced and increased dNTP pools

behavior/neurological

behavior/neurological phenotype ( J:104378 )

N • despite mitochondrial defects, mice exhibit normal muscle strength and performance

cardiovascular system

increased cardiac muscle cell glucose uptake ( J:235406 )

• in vivo uptake of glucose, the primary substrate of de novo serine biosynthesis is increased in skeletal muscle and heart

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 3		DOID:0111520	OMIM:609286	J:104378