Phenotypes associated with this allele

• Allele Symbol: Twnk^tm1.1Suom
• Allele Name: targeted mutation 1.1, Anu Suomalainen
• Allele ID: MGI:8226835
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Twnk^tm1.1Suom/Twnk^tm1.1Suom	involves: C57BL/6	MGI:8228094
cn2	Tg(Gfap-cre)73.12Mvs/0 Twnk^tm1.1Suom/Twnk^tm1.1Suom	involves: BALB/c * C57BL/6NHsd * C57BL/6JOlaHsd	MGI:8235453
cn3	Tg(Camk2a-cre)T29-1Stl/0 Twnk^tm1.1Suom/Twnk^tm1.1Suom	involves: BALB/c * C57BL * C57BL/6JOlaHsd	MGI:8235456

Genotype
MGI:8228094

hm1

• Allelic Composition: Twnk^tm1.1Suom/Twnk^tm1.1Suom
• Genetic Background: involves: C57BL/6

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

behavior/neurological

environmentally induced seizures ( J:235406 )

♂ • 5 of 21 males at 6 months of age present with generalized epileptic seizures induced by handling

♂ • however, mice show no apparent motor or sensory defects

cellular

decreased mitochondrial DNA content ( J:235406 )

• decrease in mtDNA copy numbers in the liver, but not in other tissues

growth/size/body

weight loss ( J:235406 )

• mice weigh less from 9 months of age

homeostasis/metabolism

increased carbon dioxide production ( J:235406 )

• mice produce more CO2 at thermoneutral temperature at 17 months of age

increased oxygen consumption ( J:235406 )

• mice consume more oxygen at thermoneutral temperature at 17 months of age

liver/biliary system

abnormal hepatocyte morphology ( J:235406 )

• hepatocytes show degenerative vacuolization indicative of hepatopathy

• hepatocytes show decreased lipid content

muscle

abnormal muscle morphology ( J:235406 )

• muscle shows low amino acid levels

• muscle shows a dNTP pool imbalance with generally decreased concentrations of all dNTPs

nervous system

environmentally induced seizures ( J:235406 )

♂ • 5 of 21 males at 6 months of age present with generalized epileptic seizures induced by handling

♂ • however, mice show no apparent motor or sensory defects

abnormal Purkinje cell dendrite morphology ( J:235406 )

• cerebellar Purkinje neurons show reduced arborization of the dendritic trees

decreased Purkinje cell number ( J:235406 )

• cerebellar Purkinje neurons are decreased in number

abnormal hippocampal pyramidal neuron dendrite morphology ( J:235406 )

• the hippocampal pyramidal neuron layer in the CA1 region shows decreased neurite density and disorganization of the apical dendritic trees without a reduction in neuronal number

• however, other hippocampal regions, deep gray matter nuclei, and cortical neurons show no changes

neurodegeneration ( J:235406 )

• brains show progressive neurodegeneration at 19 months of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
mitochondrial DNA depletion syndrome 7		DOID:0080126	OMIM:271245	J:235406

Genotype
MGI:8235453

cn2

• Allelic Composition: Tg(Gfap-cre)73.12Mvs/0; Twnk^tm1.1Suom/Twnk^tm1.1Suom
• Genetic Background: involves: BALB/c * C57BL/6NHsd * C57BL/6JOlaHsd

mortality/aging

increased susceptibility to xenobiotic induced morbidity/mortality ( J:304258 )

• mice treated with the mTORC1 inhibitor rapamycin at 1.5 months of age start to lose weight after only 2 weeks of age and reach humane end point at 2.3 months of age

• mice treated with rapamycin starting at 3 months of age show weight loss at already the third day of treatment and reach human end point 2 weeks after treatment initiation

premature death ( J:304258 )

• mice reach humane end point by 5-6 months of age

• mice fed a ketogenic diet after weaning before disease manifestation reach humane end point after 9.5 weeks of treatment

growth/size/body

weight loss ( J:304258 )

• mice show progressive weight loss starting from 2-3 months of age

• mice treated with the mTORC1 inhibitor rapamycin at 1.5 months of age start to lose weight after only 2 weeks of age and mice treated with rapamycin starting at 3 months of age show weight loss at already the third day of treatment

homeostasis/metabolism

abnormal homeostasis ( J:304258 )

• saccharopine, the degradation produce of lysine, is the most significantly increased metabolite

• rapamycin treatment partially rescues the saccaropine increase

• the level of sacccharopine is further increased in ketogenic diet-fed mice

decreased aspartic acid level ( J:304258 )

• aspartate levels are reduced in the brain

• aspartate, produced in the mitochondria, is decreased in ketogenic diet-fed mice

increased glycine level ( J:304258 )

• 3.6-fold increase of glycine in the brain

• the elevated glycine level is normalized by rapamycin treatment

• level of glycine is further increased in ketogenic diet-fed mice

increased proline level ( J:304258 )

• increase in proline levels in the brain

increased serine level ( J:304258 )

• 4.5- and 3.6-fold increase of serine and glycine in the brain, indicating induction of de novo serine biosynthesis

• the elevated serine level is normalized by rapamycin treatment

• level of serine is further increased in ketogenic diet-fed mice, despite de novo serine synthesis enzyme expression levels not being detected

abnormal enzyme/coenzyme level ( J:304258 )

• mice show increased expression of transsulfuration enzymes

• expression of transsulfuration enzymes is increased in ketogenic diet-fed mice

abnormal lipid metabolism ( J:304258 )

• several lipid metabolites are slightly decreased in the brain

• rapamycin has no effect on lipid metabolites in the brain

abnormal nucleotide metabolism ( J:304258 )

• several purine precursors or degradation products are increased in the brain

• uracil, a pyrimidine metabolite, is increased in the brain

• ATP, ADP, UDP, and FAD decline in ketogenic diet-fed mutant mice but not in controls, indicating an imbalance of nucleotide metabolism and high-energy phosphate donors

increased susceptibility to xenobiotic induced morbidity/mortality ( J:304258 )

• mice treated with the mTORC1 inhibitor rapamycin at 1.5 months of age start to lose weight after only 2 weeks of age and reach humane end point at 2.3 months of age

• mice treated with rapamycin starting at 3 months of age show weight loss at already the third day of treatment and reach human end point 2 weeks after treatment initiation

increased physiological sensitivity to xenobiotic ( J:304258 )

• treatment with rapamycin exacerbates spongiosis, gliosis and mitochondrial integrated stress response in the brain

• rapamycin treatment increases methionine levels and glutamine levels, suggesting either increased production or decreased usage

nervous system

gliosis ( J:304258 )

• progression of reactive gliosis is unaffected by rapamycin

• mice fed a ketogenic diet after weaning before disease manifestation show more severe gliosis than in mice fed a chow diet

spongiform encephalopathy ( J:304258 )

• 2.3-month-old mice show sparsely located holes in the brain parenchyma

• rapamycin treatment started at 1.5 months or 3 months of age does not improve but increases progression of mitochondrial spongiotic encephalopathy

• mice fed a ketogenic diet after weaning before disease manifestation, show worsening of brain pathology, with more severe spongiosis and gliosis than in mice fed a chow diet

cellular

gliosis ( J:304258 )

• progression of reactive gliosis is unaffected by rapamycin

• mice fed a ketogenic diet after weaning before disease manifestation show more severe gliosis than in mice fed a chow diet

abnormal mitochondrial physiology ( J:304258 )

• mitochondrial integrated stress response, as indicated by activation of related genes, is induced in the brain of 5.5-month-old mice but not in 2.3-month-old mice

• mice fed a ketogenic diet show further induction of the mitochondrial integrated stress response

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
mitochondrial DNA depletion syndrome		DOID:0070329	OMIM:PS603041	J:304258

Genotype
MGI:8235456

cn3

• Allelic Composition: Tg(Camk2a-cre)T29-1Stl/0; Twnk^tm1.1Suom/Twnk^tm1.1Suom
• Genetic Background: involves: BALB/c * C57BL * C57BL/6JOlaHsd

homeostasis/metabolism

decreased aspartic acid level ( J:304258 )

• reduction in aspartate levels in the brain

increased proline level ( J:304258 )

• increase in proline levels in the brain

cellular

cellular phenotype ( J:304258 )

N • mitochondrial integrated stress response is not induced in the brain at 3.5 or 7.5 months of age

nervous system

nervous system phenotype ( J:304258 )

N • mice appear healthy and do not develop mitochondrial spongiotic encephalopathy