Phenotypes associated with this allele

• Allele Symbol: Ppargc1a^tm1Brsp
• Allele Name: targeted mutation 1, Bruce M Spiegelman
• Allele ID: MGI:3511352
• Summary: 6 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Ppargc1a^tm1Brsp/Ppargc1a^tm1Brsp	involves: 129 * FVB/N	MGI:5576902
hm2	Ppargc1a^tm1Brsp/Ppargc1a^tm1Brsp	involves: 129/Sv * C57BL/6 * FVB/N	MGI:3511770
ht3	Ppargc1a^tm1Brsp/Ppargc1a^+	involves: 129 * FVB/N	MGI:5576901
ht4	Ppargc1a^tm1Brsp/Ppargc1a^+	involves: 129S4/SvJae * C57BL/6	MGI:6389045
cn5	Ppargc1a^tm1Brsp/Ppargc1a^tm2Brsp Tg(Myog-cre)1Eno/0	involves: 129 * C57BL/6 * FVB/N	MGI:5576899
cx6	Mirc33^tm1.1Wtsi/Mirc33^tm1.1Wtsi Ppargc1a^tm1Brsp/Ppargc1a^+	involves: 129S4/SvJae * C57BL/6N	MGI:6367623

Genotype
MGI:5576902

hm1

• Allelic Composition: Ppargc1a^tm1Brsp/Ppargc1a^tm1Brsp
• Genetic Background: involves: 129 * FVB/N

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

Ppargc1a^tm1Brsp/Ppargc1a^tm1Brsp mice develop dilated cardiomyopathy in response to transverse aortic constriciton (TAC)

cardiovascular system

increased heart weight ( J:111072 )

• hearts from mutants subjected to transverse aortic constriction are more increased in weight and dilated than wild-type

increased response of heart to induced stress ( J:111072 )

• 2 months after transverse aortic constriction (TAC), develop profound cardiac dysfunction, with hearts becoming dilated and showing impaired ability to contract

congestive heart failure ( J:111072 )

• TAC leads to accelerated cardiac dysfunction, accompanied by signs of heart failure

immune system

increased interleukin-6 secretion ( J:127403 )

• in myotubes

growth/size/body

increased heart weight ( J:111072 )

• hearts from mutants subjected to transverse aortic constriction are more increased in weight and dilated than wild-type

cachexia ( J:111072 )

• 2 months after TAC, mutants are visibly emaciated and show significant drops in weight, unlike wild-type

increased lung weight ( J:111072 )

• lungs are nearly quadrupled in weight 2 months after TAC as compared with only a moderate increase in wild-type TAC mice

homeostasis/metabolism

increased response of heart to induced stress ( J:111072 )

• 2 months after transverse aortic constriction (TAC), develop profound cardiac dysfunction, with hearts becoming dilated and showing impaired ability to contract

respiratory system

increased lung weight ( J:111072 )

• lungs are nearly quadrupled in weight 2 months after TAC as compared with only a moderate increase in wild-type TAC mice

Genotype
MGI:3511770

hm2

• Allelic Composition: Ppargc1a^tm1Brsp/Ppargc1a^tm1Brsp
• Genetic Background: involves: 129/Sv * C57BL/6 * FVB/N

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:93896 )

• homozygotes die when exposed to 4^oC for more than 6 hours

postnatal lethality, incomplete penetrance ( J:93896 )

• about 50% of homozygotes die during the postnatal period

adipose tissue

abnormal brown adipose tissue morphology ( J:93896 )

• abundant, large lipid droplets are seen in the brown fat

behavior/neurological

anhedonia ( J:213551 )

• mice exhibit decreased sucrose consumption as compared to wild-type mice

• sucrose consumption is decreased further following administration of kynurenine (KYN)

increased startle reflex ( J:93896 )

• an exaggerated startle response is seen

limb grasping ( J:93896 )

dystonia ( J:93896 )

• dystonic posturing is seen

hyperactivity ( J:93896 )

• a 40% increase in the frequency of random movements is seen

myoclonus ( J:93896 )

• stimulus induced myoclonus is seen

cellular

abnormal cellular respiration ( J:93896 )

• respiration due to mitochondrial proton leak is increased 20% in primary hepatocytes

homeostasis/metabolism

decreased susceptibility to diet-induced obesity ( J:93896 )

• on a high fat diet homozygous mutants are significantly leaner compared to wild-type mice

impaired adaptive thermogenesis ( J:93896 )

• mutants are unable to maintain body temperature in response to cold temperatures developing lethal hypothermia when exposed to 4^oC for more than 6 hours

increased oxygen consumption ( J:93896 )

• total oxygen consumption is increased 17% in primary hepaotcytes

• on a high fat diet oxygen consumption is increased 23% compared to wild-type mice

abnormal glucose homeostasis ( J:93896 )

hypoglycemia ( J:93896 )

• fasted mutants develop mild hypoglycemia after 24 hours

decreased circulating insulin level ( J:93896 )

• fed but not fasted mutants have decreased insulin levels relative to fed or fasted wild-type mice, respectively

abnormal gluconeogenesis ( J:93896 )

• conversion of pyruvate into glucose is reduced following intraperitoneal pyruvate injection

improved glucose tolerance ( J:93896 )

• on a high fat diet homozygous mutants have significantly increased glucose tolerance compared to wild-type mice

increased insulin sensitivity ( J:93896 )

• on a high fat diet homozygous mutants have significantly increased insulin sensitivity compared to wild-type mice

abnormal lipid homeostasis ( J:93896 )

decreased liver triglyceride level ( J:93896 )

• triglyceride levels are lower in the livers of fasted mutant mice

muscle

dystonia ( J:93896 )

• dystonic posturing is seen

myoclonus ( J:93896 )

• stimulus induced myoclonus is seen

nervous system

myoclonus ( J:93896 )

• stimulus induced myoclonus is seen

gliosis ( J:93896 )

• gliosis is seen associated with the spongiform lesions

abnormal neuron morphology ( J:93896 )

• striatal neurons with reduced branches of neurites and occasional vacuoles within the neurons are seen

spongiform encephalopathy ( J:93896 )

• spongiform lesions are seen predominantly in the striatum and to a lesser extent in the cortex

• the lesions are mostly associated with the white matter

growth/size/body

decreased susceptibility to diet-induced obesity ( J:93896 )

• on a high fat diet homozygous mutants are significantly leaner compared to wild-type mice

liver/biliary system

decreased liver triglyceride level ( J:93896 )

• triglyceride levels are lower in the livers of fasted mutant mice

Genotype
MGI:5576901

ht3

• Allelic Composition: Ppargc1a^tm1Brsp/Ppargc1a⁺
• Genetic Background: involves: 129 * FVB/N

immune system

immune system phenotype ( J:127403 )

N • mice exhibit normal serum IL6 levels

Genotype
MGI:6389045

ht4

• Allelic Composition: Ppargc1a^tm1Brsp/Ppargc1a⁺
• Genetic Background: involves: 129S4/SvJae * C57BL/6

vision/eye

abnormal choroid vasculature morphology ( J:264271 )

• mice fed a regular diet show enlarged blood vessels in the interface between the Bruch's membrane and the choroid, with congestion and dilatation of some vessels

abnormal choriocapillaris morphology ( J:264271 )

• mice fed a high-fat diet show a greater loss of fenestration in choriocapillaris endothelium

short photoreceptor inner segment ( J:264271 )

• mice fed a regular diet and a high-fat diet show a reduction of thickness of the inner segment layer

short photoreceptor outer segment ( J:264271 )

• mice fed a regular diet and a high-fat diet show a reduction of thickness of the outer segment layer

retina photoreceptor degeneration ( J:264271 )

• mice fed a high-fat diet exhibit a thinner photoreceptor layer, indicating degeneration of this layer

• photoreceptor degeneration does not necessarily initiate concurrently in both eyes

abnormal retina pigment epithelium morphology ( J:264271 )

• mice fed a regular diet show higher numbers of lipofuscin deposits in the retinal pigment epithelium (RPE) than wild-type mice

• mice fed a high-fat diet show a greater accumulation of lipofuscin in the cytoplasm of the RPE, basal laminar deposits, and thickening of the outer collagenous layer

• mice fed a high-fat diet show RPE retinal pigment epithelium degeneration, with disruptions or gaps and scant melanosomes in the subretinal space migrating into the outer segment

retina macular degeneration ( J:264271 )

• mice fed a high-fat diet present age-related macular degeneration-like abnormalities in the retinal pigment epithelium and retinal morphology and function

abnormal Bruch membrane morphology ( J:264271 )

• mice fed a high-fat diet show changes in the Bruch membrane, either atrophy or thickening in various regions

• mice fed a high-fat diet show accumulation of carboxymethyl lysine (CML) deposits in the thickened Bruch membrane, indicating oxidative damage

immune system

increased inflammatory response ( J:264271 )

• lipopolysaccharide (LPS) injection induces a higher inflammatory response in the retinal pigment epithelium (RPE)/retina compared to in wild-type mice

cardiovascular system

abnormal choroid vasculature morphology ( J:264271 )

• mice fed a regular diet show enlarged blood vessels in the interface between the Bruch's membrane and the choroid, with congestion and dilatation of some vessels

abnormal choriocapillaris morphology ( J:264271 )

• mice fed a high-fat diet show a greater loss of fenestration in choriocapillaris endothelium

homeostasis/metabolism

impaired autophagy ( J:264271 )

• autophagy is reduced in the retinal pigment epithelium/retina

nervous system

short photoreceptor inner segment ( J:264271 )

• mice fed a regular diet and a high-fat diet show a reduction of thickness of the inner segment layer

short photoreceptor outer segment ( J:264271 )

• mice fed a regular diet and a high-fat diet show a reduction of thickness of the outer segment layer

retina photoreceptor degeneration ( J:264271 )

• mice fed a high-fat diet exhibit a thinner photoreceptor layer, indicating degeneration of this layer

• photoreceptor degeneration does not necessarily initiate concurrently in both eyes

pigmentation

abnormal retina pigment epithelium morphology ( J:264271 )

• mice fed a regular diet show higher numbers of lipofuscin deposits in the retinal pigment epithelium (RPE) than wild-type mice

• mice fed a high-fat diet show a greater accumulation of lipofuscin in the cytoplasm of the RPE, basal laminar deposits, and thickening of the outer collagenous layer

• mice fed a high-fat diet show RPE retinal pigment epithelium degeneration, with disruptions or gaps and scant melanosomes in the subretinal space migrating into the outer segment

abnormal melanosome transport ( J:264271 )

• mice fed a high-fat diet show scant melanosomes migrating into the outer segment

lipofuscinosis ( J:264271 )

• mice fed a regular diet show higher numbers of lipofuscin deposits than wild-type mice

• mice fed a high-fat diet show a greater accumulation of lipofuscin in the cytoplasm of the RPE

cellular

decreased mitochondrial DNA content ( J:264271 )

• mice fed a high-fat diet show a greater decrease in mtDNA copy number than wild-type mice

impaired autophagy ( J:264271 )

• autophagy is reduced in the retinal pigment epithelium/retina

abnormal mitochondrial physiology ( J:264271 )

• mice fed a high-fat diet show a greater decrease in mitochondrial complex I activity in the retinal pigment epithelium/retina

oxidative stress ( J:264271 )

• mice fed a high-fat diet show accumulation of carboxymethyl lysine deposits in the thickened Bruchs membrane, indicating oxidative damage

• mice fed a high-fat diet show increased reactive oxygen species (ROS) levels in the retinal pigment epithelium/retina

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
age related macular degeneration		DOID:10871	OMIM:PS603075	J:264271

Genotype
MGI:5576899

cn5

• Allelic Composition: Ppargc1a^tm1Brsp/Ppargc1a^tm2Brsp; Tg(Myog-cre)1Eno/0
• Genetic Background: involves: 129 * C57BL/6 * FVB/N

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:127403 )

N • mice fed standard chow or a high fat diet exhibit normal insulin tolerance

N • hepatic glucose output under basal and clamped conditions is normal

decreased susceptibility to diet-induced obesity ( J:127403 )

• in mice fed a high fat diet

increased circulating interleukin-6 level ( J:127403 )

increased oxygen consumption ( J:127403 )

• in mice fed a high fat diet

decreased respiratory quotient ( J:127403 )

• in mice fed a high fat diet

abnormal glucose homeostasis ( J:127403 )

• mice exhibit increased systemic glucose uptake and glycolysis compared with control mice

• however, glycogen synthesis is normal

increased circulating glucose level ( J:127403 )

• in fed mice on standard chow

• however, fasted mice exhibit normal blood glucose levels

hyperglycemia ( J:127403 )

• in fasted and fed mice on a high fat diet

decreased circulating insulin level ( J:127403 )

• in fed mice on standard chow or a high fat diet

impaired glucose tolerance ( J:127403 )

• in fed mice on a high fat diet

increased basal metabolism ( J:127403 )

• in mice fed a high fat diet

endocrine/exocrine glands

endocrine/exocrine gland phenotype ( J:127403 )

N • islets exhibit normal basal and glucose-stimulated insulin secretion

abnormal pancreatic beta cell morphology ( J:127403 )

• reduced cell size

increased pancreatic beta cell mass ( J:127403 )

enlarged pancreatic islets ( J:127403 )

growth/size/body

decreased body weight ( J:127403 )

• in mice fed standard chow or a high fat diet

decreased susceptibility to diet-induced obesity ( J:127403 )

• in mice fed a high fat diet

immune system

increased circulating interleukin-6 level ( J:127403 )

adipose tissue

decreased percent body fat/body weight ( J:127403 )

• in mice fed standard chow or a high fat diet

cellular

abnormal mitochondrial physiology ( J:127403 )

• decreased function as measured by Cox and succinate dehydrogenase activity

behavior/neurological

decreased food intake ( J:127403 )

• during the day and night in mice fed a high fat diet

Genotype
MGI:6367623

cx6

• Allelic Composition: Mirc33^tm1.1Wtsi/Mirc33^tm1.1Wtsi; Ppargc1a^tm1Brsp/Ppargc1a⁺
• Genetic Background: involves: 129S4/SvJae * C57BL/6N

mortality/aging

premature death ( J:267719 )

• mice exhibit a life span extension compared with single Mirc33^tm1.1Wtsi homozygotes, with a median of 39.5 weeks compared to 30 weeks, but reduced survival compared to wild-type mice

cellular

decreased mitochondrial size ( J:267719 )

• cardiac mitochondrial size is smaller

• however, cardiac mitochondrial DNA levels and mitochondrial numbers are restored to wild-type levels

cardiovascular system

cardiovascular system phenotype ( J:267719 )

N • mice show a reduction in systemic blood pressure compared to single Mirc33^tm1.1Wtsi homozygotes