Phenotypes Associated with This Genotype

Genotype
MGI:7316678

• Allelic Composition: Serac1^em1Bcgen/Serac1^em1Bcgen
• Genetic Background: C57BL/6N-Serac1^em1Bcgen

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

behavior/neurological

decreased grip strength ( J:326672 )

• both young and adult males and females show lower forelimb grip strength

• oral dNTP supplementation improves forelimb grip strength

cardiovascular system

enlarged heart ( J:326672 )

decreased heart left ventricle wall thickness ( J:326672 )

cardiomyopathy ( J:326672 )

• mice exhibit enlarged hearts with lower left ventricular wall thickness

cellular

decreased mitochondrial DNA content ( J:326672 )

• lower mtDNA content in the liver, skeletal muscle, and brain

• oral dNTP supplementation increases mtDNA content in the liver

decreased hepatocyte mitochondrial DNA content ( J:326672 )

decreased skeletal muscle fiber mitochondrial DNA content ( J:326672 )

decreased mitochondrial size ( J:326672 )

• in the liver

increased mitochondrial number ( J:326672 )

• in the liver

abnormal cellular respiration ( J:326672 )

• primary hepatocytes exhibit impaired mitochondrial respiration

abnormal mitochondrial fission ( J:326672 )

• mitochondrial fission machinery is not induced in the liver

abnormal oxidative phosphorylation ( J:326672 )

• mice show impaired mitochondrial oxidative phosphorylation: liver shows a reduction in mitochondrial CIII and V activity and impaired mitochondrial respiratory chain supercomplex assembly at 1 month of age

• brain and skeletal muscle show impaired mitochondrial supercomplex assembly at 6 months, but not 3 months, of age

• oral dNTP supplementation restores activity of subunits CI and CIV and partially rescues activity of CIII in the liver

hearing/vestibular/ear

increased or absent threshold for auditory brainstem response ( J:326672 )

• males show increased auditory brainstem response threshold to click noises at 3 and 6 months of age

impaired hearing ( J:326672 )

• adult and middle-aged male mice exhibit a hearing impairment

homeostasis/metabolism

decreased circulating cholesterol level ( J:326672 )

increased liver glycogen level ( J:326672 )

• 1- to 6-month-old mice show an increased accumulation of hepatic glycogen

• the increase in hepatic glycogen is abolished by oral dNTP supplementation

increased liver cholesterol level ( J:326672 )

• mice show increased accumulation of hepatic cholesterol over time

• the increase in hepatic cholesterol is abolished by oral dNTP supplementation

increased liver triglyceride level ( J:326672 )

• accumulation of triacylglycerol in the liver

• the accumulation of triacylglycerol in the liver is partially reduced by oral dNTP supplementation

aciduria ( J:326672 )

• young and adult males have higher urinary 3-methylglutaconic acid (3-MGA) content indicating urinary 3-methylgutaconic aciduria

liver/biliary system

abnormal liver morphology ( J:326672 )

• mice show a late-onset lipid accumulation by 12 months of age

• liver shows fragmented and shrunken mitochondria

• number of mitochondria is higher in the liver

• however, hepatic lipid accumulation is not seen at 1 or 6 months

• however, hepatic fibrosis is not seen in 1- to 12-month-old mice

• decrease of phosphatidylglycerol (34:1) content in the liver at 2.5 months

• oral dNTP supplementation improves mitochondrial cristae structure and slightly improves mitochondrial morphology

increased liver glycogen level ( J:326672 )

• 1- to 6-month-old mice show an increased accumulation of hepatic glycogen

• the increase in hepatic glycogen is abolished by oral dNTP supplementation

increased liver cholesterol level ( J:326672 )

• mice show increased accumulation of hepatic cholesterol over time

• the increase in hepatic cholesterol is abolished by oral dNTP supplementation

increased liver triglyceride level ( J:326672 )

• accumulation of triacylglycerol in the liver

• the accumulation of triacylglycerol in the liver is partially reduced by oral dNTP supplementation

abnormal hepatocyte morphology ( J:326672 )

• hepatic cell edema occurs as early as 1 month of age and an advanced phenotype with damaged hepatic cells is seen at 12 months of age

decreased hepatocyte mitochondrial DNA content ( J:326672 )

muscle

cardiomyopathy ( J:326672 )

• mice exhibit enlarged hearts with lower left ventricular wall thickness

abnormal muscle fiber morphology ( J:326672 )

• decrease in the whole muscle cross-sectional area, including both fast and slow muscle fibers, and an increase in the slow to fast muscle fiber ratio

decreased skeletal muscle fiber mitochondrial DNA content ( J:326672 )

muscle weakness ( J:326672 )

• mice held a suspension rope with either the tail or hindlimb more poorly than wild-type mice in a modified forelimb suspension test, indicating decreased muscle strength

• mice supplemented with deoxy-ribonucleoside triphosphate (dNTP) via drinking water showed improved performance on the pole test, in the beam walking paw slip test, and the rotarod test

nervous system

abnormal basal ganglion morphology ( J:326672 )

• 12-month-old mice exhibit lesions in the basal ganglia

• percentage of IBA1-labeled microglia in basal ganglia of 6-month-old mice is lower

brain lesion ( J:326672 )

• brain lesions are reminiscent of metabolic encephalopathy and mice develop a Leigh-like syndrome

encephalopathy ( J:326672 )

• brain lesions are associated with higher lactic acid content in the brain and a reminiscent of metabolic encephalopathy

renal/urinary system

aciduria ( J:326672 )

• young and adult males have higher urinary 3-methylglutaconic acid (3-MGA) content indicating urinary 3-methylgutaconic aciduria

reproductive system

reproductive system phenotype ( J:326672 )

N • male fecundity does not appear to be affected

growth/size/body

enlarged heart ( J:326672 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome		DOID:0110001	OMIM:614739	J:326672