Phenotypes Associated with This Genotype

Genotype
MGI:7596076

• Allelic Composition: Sdhaf4^em1Bcgen/Sdhaf4^em1Bcgen; Tg(Ckmm-cre)5Khn/0
• Genetic Background: B6.Cg-Sdhaf4^em1Bcgen Tg(Ckmm-cre)5Khn

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

mortality/aging

premature death ( J:345348 )

• none survive past 12 weeks of age

• treatment with sodium fumarate dibasic or Mdivi-1 (a specific Dnm1l inhibitor) to target mitochondria substantially prolongs the survival of the mice

cardiovascular system

abnormal myocardial fiber morphology ( J:345348 )

• severe abnormalities in myofibril/sarcomere organization and intramitochondrial structure at 8 weeks of age

abnormal myocardial fiber mitochondrial morphology ( J:345348 )

• despite the increase in number of mitochondria the amount of mtDNA is reduced

• at 8 weeks of age cristae malformations, electron-dense inclusions and hypodense compartments are seen

• at 8 weeks of age the number of mitochondria is increased and the size is decreased

• treatment with sodium fumarate dibasic or Mdivi-1 (a specific Dnm1l inhibitor) improves mitochondrial morphology

decreased myocardial fiber mitochondrial DNA content ( J:345348 )

• in cardiomyocytes at 8 weeks of age

thick myocardium ( J:345348 )

• thickening of the cardiac muscle by 3-4 weeks of age

enlarged heart ( J:345348 )

increased heart weight ( J:345348 )

• starting at 3 weeks of age

dilated heart ventricle ( J:345348 )

• develops at later stages

cardiac fibrosis ( J:345348 )

• present at 7 weeks but not at 4 weeks of age

dilated cardiomyopathy ( J:345348 )

• at later stages

• upregulation of pathological markers is seen primarily in the left ventricle

abnormal cardiac muscle contractility ( J:345348 )

• deregulated cardiac contraction

• treatment with Mdivi-1 (a specific Dnm1l inhibitor) improves cardiac function

decreased heart left ventricle muscle contractility ( J:345348 )

• decrease in left ventricular fractional shortening

growth/size/body

enlarged heart ( J:345348 )

increased heart weight ( J:345348 )

• starting at 3 weeks of age

decreased body weight ( J:345348 )

• lower body weights in mice older than 6 weeks

• no difference in body weight is detected during the first 6 weeks of life

• ratio of tibialis anterior muscle weight to body weight is similar to controls

cellular

abnormal myocardial fiber mitochondrial morphology ( J:345348 )

• at 8 weeks of age cristae malformations, electron-dense inclusions and hypodense compartments are seen

• at 8 weeks of age the number of mitochondria is increased and the size is decreased

• despite the increase in number of mitochondria the amount of mtDNA is reduced

• treatment with sodium fumarate dibasic or Mdivi-1 (a specific Dnm1l inhibitor) improves mitochondrial morphology

decreased myocardial fiber mitochondrial DNA content ( J:345348 )

• in cardiomyocytes at 8 weeks of age

abnormal mitochondrial physiology ( J:345348 )

• mitochondrial dysfunction in the heart indicated by expression analysis, increase in protein oxidation, and decreases in TCA cycle related metabolites

• analysis of posttranslational modification of Dnm1l and other results suggest an increase in mitochondrial fission

abnormal tricarboxylic acid cycle ( J:345348 )

• deregulated TCA cycle in cardiomyocytes

muscle

abnormal myocardial fiber morphology ( J:345348 )

• severe abnormalities in myofibril/sarcomere organization and intramitochondrial structure at 8 weeks of age

abnormal myocardial fiber mitochondrial morphology ( J:345348 )

• at 8 weeks of age cristae malformations, electron-dense inclusions and hypodense compartments are seen

• at 8 weeks of age the number of mitochondria is increased and the size is decreased

• despite the increase in number of mitochondria the amount of mtDNA is reduced

• treatment with sodium fumarate dibasic or Mdivi-1 (a specific Dnm1l inhibitor) improves mitochondrial morphology

decreased myocardial fiber mitochondrial DNA content ( J:345348 )

• in cardiomyocytes at 8 weeks of age

thick myocardium ( J:345348 )

• thickening of the cardiac muscle by 3-4 weeks of age

dilated cardiomyopathy ( J:345348 )

• at later stages

• upregulation of pathological markers is seen primarily in the left ventricle

abnormal cardiac muscle contractility ( J:345348 )

• deregulated cardiac contraction

• treatment with Mdivi-1 (a specific Dnm1l inhibitor) improves cardiac function

decreased heart left ventricle muscle contractility ( J:345348 )

• decrease in left ventricular fractional shortening

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
dilated cardiomyopathy		DOID:12930	OMIM:PS115200	J:345348