Phenotypes associated with this allele

• Allele Symbol: Pnpla2^tm1Rze
• Allele Name: targeted mutation 1, Rudolf Zechner
• Allele ID: MGI:3629035
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Pnpla2^tm1Rze/Pnpla2^tm1Rze	involves: 129P2/OlaHsd	MGI:5007483
hm2	Pnpla2^tm1Rze/Pnpla2^tm1Rze	involves: 129P2/OlaHsd * C57BL/6	MGI:3629097
cx3	Pnpla2^tm1Rze/Pnpla2^tm1Rze Tg(Myh6-Pnpla2)94Biat/0	involves: 129P2/OlaHsd * C57BL/6 * DBA/2	MGI:5294406

Genotype
MGI:5007483

hm1

• Allelic Composition: Pnpla2^tm1Rze/Pnpla2^tm1Rze
• Genetic Background: involves: 129P2/OlaHsd

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

Increase in neutral lipid content in Abhd5^tm1.1Rze/Abhd5^tm1.1Rze and Pnpla2^tm1Rze/Pnpla2^tm1Rze livers

mortality/aging

premature death ( J:176252 )

• however, treatment with Wy14643 exhibit increased survival

cardiovascular system

abnormal cardiovascular system morphology ( J:176252 )

• treatment with GW501516 or GW0742 (PPARG agonists) fail to improve cardiometabolic defects

• however, treatment with Wy14643 (PPARA agonist) rescues cardiometabolic defects

increased cardiac muscle glycogen level ( J:176252 )

abnormal myocardial fiber morphology ( J:176252 )

• cardiomyocytes exhibit increased size and number of lipid droplets and glycogen granules compared to in wild-type muscles

• cardiomyocytes exhibit increased mitochondria size with decreased mitochondrial DNA compared to in wild-type muscles

• however, treatment with Wy14643 (PPARA agonist) restores mitochondrial size and membrane potential

abnormal myocardial fiber mitochondrial morphology ( J:176252 )

• cardiomyocytes exhibit increased mitochondria size with decreased mitochondrial DNA compared to in wild-type muscles

• however, treatment with Wy14643 (PPARA agonist) restores mitochondrial size and membrane potential

cardiac hypertrophy ( J:176252 )

• concentric hypertrophy

abnormal heart ventricle morphology ( J:176252 )

• thickened posterior wall

• lower left ventricular end-diastolic dimensions

thick interventricular septum ( J:176252 )

• however, treatment with Wy14643 (PPARA agonist) reduces interventricular septum thickness

increased heart left ventricle weight ( J:176252 )

• however, treatment with Wy14643 (PPARA agonist) restores normal left ventricle weight

decreased heart ventricle muscle contractility ( J:176252 )

• mice exhibit reduced ventricular fractional shortening and ejection fraction compared with wild-type mice

• however, treatment with Wy14643 (PPARA agonist) restores fractional shortening and ejection fraction

increased heart rate ( J:176252 )

• however, treatment with Wy14643 (PPARA agonist) reduces heart rate

abnormal myocardial fiber physiology ( J:176252 )

• cardiomyocytes exhibit reduced oxidative capacity compared with wild-type mice

homeostasis/metabolism

increased cardiac muscle glycogen level ( J:176252 )

decreased oxygen consumption ( J:176252 )

• in heart homogenate mitochondria under basal and succinate-stimulated conditions

• however, treatment with Wy14643 (PPARA agonist) restores oxygen consumptions

abnormal respiratory quotient ( J:176252 )

• during the light period or food deprivation, mice exhibit less of a decrease in respiratory quotient compared with wild-type mice

increased respiratory quotient ( J:176252 )

abnormal lipid homeostasis ( J:160725 )

• mouse embryonic fibroblasts treated with oleic acid to induce lipogenesis exhibit a 1.9-fold increase in triglyceride accumulation compared with similarly treated wild-type cells

decreased circulating free fatty acids level ( J:176252 )

decreased circulating triglyceride level ( J:176252 )

increased fatty acids level ( J:176252 )

• mice exhibit a 53% increase in total intracellular concentration of unesterified fatty acid in the heart compared with wild-type mice

increased triglyceride level ( J:160725 , J:176252 )

• 4.6-fold in the livers of newborn mice (J:160725)

• 1.6-fold in the dermal (J:160725)

• 1.3-fold in epidermis (J:160725)

• in cardiac and liver muscles (J:176252)

• 4.6-fold higher in older mice than in younger mice (J:176252)

• however, treatment with Wy14643 or fenofibrate (PPARA agonists) restores normal triglyceride levels (J:176252)

increased liver triglyceride level ( J:160725 , J:176252 )

• 4.6-fold in the livers of newborn mice (J:160725)

• however, treatment with Wy14643 or fenofibrate (PPARA agonists) reduces triglyceride levels (J:176252)

abnormal metabolism ( J:176252 )

• treatment with GW501516 or GW0742 (PPARG agonists) fail to improve cardiometabolic defects

• however, treatment with Wy14643 (PPARA agonist) rescues cardiometabolic defects

abnormal enzyme/coenzyme activity ( J:160725 )

• mouse embryonic fibroblasts exhibit decreased triglyceride hydrolase activity compared with wild-type cells

• liver and skin triglyceride hydrolase activity is decreased compared to in wild-type mice

• however, epidermal triglyceride hydrolase activity is normal

impaired lipolysis ( J:160725 )

• mouse embryonic fibroblasts exhibit decreased triglyceride hydrolase activity compared with wild-type cells

• liver and skin triglyceride hydrolase activity is decreased compared to in wild-type mice

• however, epidermal triglyceride hydrolase activity is normal

adipose tissue

increased brown adipose tissue amount ( J:176252 )

increased white adipose tissue amount ( J:176252 )

cellular

abnormal myocardial fiber mitochondrial morphology ( J:176252 )

• cardiomyocytes exhibit increased mitochondria size with decreased mitochondrial DNA compared to in wild-type muscles

• however, treatment with Wy14643 (PPARA agonist) restores mitochondrial size and membrane potential

liver/biliary system

increased liver triglyceride level ( J:160725 , J:176252 )

• 4.6-fold in the livers of newborn mice (J:160725)

• however, treatment with Wy14643 or fenofibrate (PPARA agonists) reduces triglyceride levels (J:176252)

integument

integument phenotype ( J:160725 )

N • mice exhibit normal skin barrier function

muscle

increased cardiac muscle glycogen level ( J:176252 )

abnormal myocardial fiber morphology ( J:176252 )

• cardiomyocytes exhibit increased size and number of lipid droplets and glycogen granules compared to in wild-type muscles

• cardiomyocytes exhibit increased mitochondria size with decreased mitochondrial DNA compared to in wild-type muscles

• however, treatment with Wy14643 (PPARA agonist) restores mitochondrial size and membrane potential

abnormal myocardial fiber mitochondrial morphology ( J:176252 )

• cardiomyocytes exhibit increased mitochondria size with decreased mitochondrial DNA compared to in wild-type muscles

• however, treatment with Wy14643 (PPARA agonist) restores mitochondrial size and membrane potential

decreased heart ventricle muscle contractility ( J:176252 )

• mice exhibit reduced ventricular fractional shortening and ejection fraction compared with wild-type mice

• however, treatment with Wy14643 (PPARA agonist) restores fractional shortening and ejection fraction

growth/size/body

cardiac hypertrophy ( J:176252 )

• concentric hypertrophy

Genotype
MGI:3629097

hm2

• Allelic Composition: Pnpla2^tm1Rze/Pnpla2^tm1Rze
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

mortality/aging

premature death ( J:108546 )

• pronounced cardiac dysfunction results in premature death for male and female homozygotes; the first mice die around 12 weeks of age

• male mice (50% after 16 weeks) die earlier than female (50% after 20 weeks)

• heterozygous mice have normal life spans

growth/size/body

increased heart weight ( J:108546 )

• mutant hearts have a 1.4x heart weight because of the excess triglycerides (193 mg for mutant vs 131 mg wild-type)

increased body mass index ( J:108546 )

• homozygotes display a 2-fold increase in body fat mass

increased body weight ( J:108546 )

• homozygotes are heavier than wild-type

homeostasis/metabolism

abnormal homeostasis ( J:108546 )

impaired adaptive thermogenesis ( J:108546 )

• after 5 hours of cold exposure, mutant body temperature is only 25 degrees C

• when mutants are exposed to cold for 5 hours, they suffer from life-threatening hypothermia as a result of impaired catabolism to triglycerides to brown adipose tissue

• after 18 hours of fasting, body temperature drops to 28.4 degrees C vs 35.4 degrees in wild-type with prolonged fasting

abnormal circulating glucose level ( J:108546 )

decreased circulating glucose level ( J:108546 )

• after a 6-hour fast, mice have significantly lower basal glucose values compared to wild-type

abnormal circulating hormone level ( J:108546 )

abnormal circulating insulin level ( J:108546 )

decreased circulating insulin level ( J:108546 )

• in the fed state, plasma insulin levels are reduced by 42% in mutants compared to wild-type

increased circulating leptin level ( J:108546 )

• plasma leptin levels are elevated by 2.1-fold in fed mutants and by 4.4-fold in fasted mutant mice

cardiac edema ( J:108546 )

• at death

abnormal gas homeostasis ( J:108546 )

decreased oxygen consumption ( J:108546 )

• oxygen consumption decreases to 25% of that of wild-type after 18 hours of fasting

abnormal respiratory quotient ( J:108546 )

• RQ in mutants deviates from wild-type during fasting; RQ remains constant whereas in wild-type, it decreases with increasing fasting time

abnormal glucose tolerance ( J:108546 )

improved glucose tolerance ( J:108546 )

• after a 6-hour fast, null mice show improved glucose tolerance compared to wild-type

increased insulin sensitivity ( J:108546 )

• maximal decline of blood glucose levels is more pronounced (34 mg/dl vs 53 mg/dl in wild-type) in Pnpla-deficient mice and persists for the entire 3 hour observation period

abnormal lipid homeostasis ( J:108546 )

decreased circulating HDL cholesterol level ( J:108546 )

• total cholesterol (due to decreased HDL levels) is reduced by 22%

decreased circulating free fatty acids level ( J:108546 )

• in mutants, levels are reduced by 30% in the fed state and by 62% in the fasted state

decreased circulating triglyceride level ( J:108546 )

• levels are decreased by 66%

decreased circulating VLDL triglyceride level ( J:108546 )

• reduced VLDL levels are found in mutants

increased triglyceride level ( J:108546 )

• in non-cardiac tissue the most pronounced accumulation of triglycerides is a >10-fold increase seen in the testis and kidney; smaller (1.5-4-fold) increases are seen in all tissues including the liver

increased cardiac muscle triglyceride level ( J:108546 )

• there is a 20-fold increase in triglyceride content in cardiac muscle by 12 weeks of age in mutants

increased liver triglyceride level ( J:108546 )

impaired lipolysis ( J:108546 )

• in mutants there is decreased lipolytic activities in white (-82%) and brown (-85%) adipose tissues, cardiac muscle (-31%), skeletal muscle (-44%), testis (-69%) and liver (-73%)

adipose tissue

abnormal brown adipose tissue morphology ( J:108546 )

• mutant mice have enlarged lipid droplets (1395 micrometer² vs 67 micrometer² in wild-type) in brown adipocytes

increased brown adipose tissue amount ( J:108546 )

• mutants have an 8.5 fold increase in wet weight of intracapsular brown adipose tissue

increased gonadal fat pad weight ( J:108546 )

• homozygotes display a 1.6 fold increase in wet weight of gonadal white adipose tissue compared to controls

increased inguinal fat pad weight ( J:108546 )

• homozygotes display a 2.1 fold increase in wet weight of inguinal white adipose tissue compared to controls

increased interscapular fat pad weight ( J:108546 )

• mutants have an 8.5 fold increase in wet weight of intracapsular brown adipose tissue

abnormal white adipose tissue morphology ( J:108546 )

• mutant mice have enlarged lipid droplets (4690 micrometer² vs 3382 micrometer² in wild-type) in white adipocytes

cardiovascular system

pulmonary vascular congestion ( J:108546 )

• congestion is observed in pulmonary vessels at death; not observed in mice before 14 weeks of age

increased cardiac muscle triglyceride level ( J:108546 )

• there is a 20-fold increase in triglyceride content in cardiac muscle by 12 weeks of age in mutants

abnormal heart morphology ( J:108546 )

abnormal myocardium layer morphology ( J:108546 )

• in homozygotes there is severe triglyceride accumulation in cardiac muscle; at 12 weeks of age, mutants have a 20-fold higher triglyceride content in myocytes compared to wild-type

abnormal myocardial fiber morphology ( J:108546 )

• lipid droplets show an age-dependent increase in size and number in cardiomyocytes of mutants beginning with microvesicular droplets at 6 weeks and progressing to large droplets by 18 weeks

thick interventricular septum ( J:108546 )

• the interventricular septum in mutant hearts is significantly thickened and increases in thickness with age

increased heart weight ( J:108546 )

• mutant hearts have a 1.4x heart weight because of the excess triglycerides (193 mg for mutant vs 131 mg wild-type)

dilated heart left ventricle ( J:108546 )

• at death; this is not observed in mice before 14 weeks of age

dilated heart right ventricle ( J:108546 )

• at death; this is not observed in mice before 14 weeks of age

cardiac fibrosis ( J:108546 )

• there is a marked change in cardiac texture and increase in fibrosis

abnormal cardiovascular system physiology ( J:108546 )

• massive lipid buildup causes severe cardiac insufficiency in mutants

• at death, cardiac edema and pleural as well as cardiac effusions are observed; these are not observed in mice before 14 weeks of age

decreased heart left ventricle muscle contractility ( J:108546 )

• ejection fraction from left ventricle is drastically reduced compared to wild-type (40.2% vs 80.5% in wild-type)

congestive heart failure ( J:108546 )

• at death, mutants display typical features of congestive heart failure

muscle

increased cardiac muscle triglyceride level ( J:108546 )

• there is a 20-fold increase in triglyceride content in cardiac muscle by 12 weeks of age in mutants

abnormal myocardium layer morphology ( J:108546 )

• in homozygotes there is severe triglyceride accumulation in cardiac muscle; at 12 weeks of age, mutants have a 20-fold higher triglyceride content in myocytes compared to wild-type

abnormal myocardial fiber morphology ( J:108546 )

• lipid droplets show an age-dependent increase in size and number in cardiomyocytes of mutants beginning with microvesicular droplets at 6 weeks and progressing to large droplets by 18 weeks

decreased heart left ventricle muscle contractility ( J:108546 )

• ejection fraction from left ventricle is drastically reduced compared to wild-type (40.2% vs 80.5% in wild-type)

abnormal cardiomyocyte apoptosis ( J:108546 )

• in mutants there is a moderate induction of apoptosis

liver/biliary system

increased liver triglyceride level ( J:108546 )

hepatic steatosis ( J:108546 )

respiratory system

pulmonary vascular congestion ( J:108546 )

• congestion is observed in pulmonary vessels at death; not observed in mice before 14 weeks of age

cellular

abnormal cardiomyocyte apoptosis ( J:108546 )

• in mutants there is a moderate induction of apoptosis

Genotype
MGI:5294406

cx3

• Allelic Composition: Pnpla2^tm1Rze/Pnpla2^tm1Rze; Tg(Myh6-Pnpla2)94Biat/0
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6 * DBA/2

mortality/aging

mortality/aging ( J:176252 )

N • mice exhibit a normal life span

homeostasis/metabolism

decreased circulating free fatty acids level ( J:176252 )

decreased circulating triglyceride level ( J:176252 )

adipose tissue

increased brown adipose tissue amount ( J:176252 )

increased white adipose tissue amount ( J:176252 )

cardiovascular system

cardiovascular system phenotype ( J:176252 )

N • heart weight, cardiac hypertrophy, massive triglyceride accumulation, and basal and succinate-stimulated cardiac oxygen consumption are normal