Phenotypes associated with this allele

• Allele Symbol: Erp44^Gt(XB599)Byg
• Allele Name: gene trap XB599, BayGenomics
• Allele ID: MGI:4124445
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Erp44^Gt(XB599)Byg/Erp44^Gt(XB599)Byg	B6.129P2(129S)-Erp44^Gt(XB599)Byg	MGI:7493378
ht2	Erp44^Gt(XB599)Byg/Erp44^+	B6.129P2(129S)-Erp44^Gt(XB599)Byg	MGI:7493377

Genotype
MGI:7493378

hm1

• Allelic Composition: Erp44^Gt(XB599)Byg/Erp44^Gt(XB599)Byg
• Genetic Background: B6.129P2(129S)-Erp44^Gt(XB599)Byg

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

mortality/aging

premature death ( J:244948 )

• very few mice survive into adulthood; surviving mice exhibit a shortened lifespan and die around 8 to 9 months of age

preweaning lethality, incomplete penetrance ( J:244948 )

• homozygous mice exhibit significant embryonic and/or perinatal lethality

embryonic lethality during organogenesis, incomplete penetrance ( J:244948 )

• homozygous embryos show significant mortality at E9.5 to E12.5

growth/size/body

increased heart weight ( J:244948 )

• adult heart weight to body weight (HW/BW) ratios and heart weight to tibia length (HW/TL) ratios are significantly higher than in wild-type controls

cardiac hypertrophy ( J:244948 )

• adult hearts show a significant increase in the mRNA expression of the hypertrophic markers atrial natriuretic factor (Nppa/Anf) and B-type natriuretic peptide (Nppb/Bnp)

decreased body size ( J:244948 )

• surviving mice show a 40% to 50% reduction in body size relative to wild-type controls

decreased body weight ( J:244948 )

• surviving mice exhibit significantly decreased body weights at 3 weeks, 3 months, and 6 months of age

cardiovascular system

abnormal heart morphology ( J:244948 )

• H&E staining of adult hearts shows slightly abnormal cardiac morphology, with evidence of mild fibrosis and increased cell size

abnormal myocardial fiber mitochondrial morphology ( J:244948 )

• EM analysis of heart sections shows mitochondrial membrane rupture and a significant increase in mitochondrial size in late-stage mice

increased myocardial fiber size ( J:244948 )

• wheat germ agglutinin (WGA) staining of adult hearts shows a significant increase in cardiac cell area relative to wild-type hearts

myocardial fiber disarray ( J:244948 )

• EM analysis of heart sections shows significant myocyte swelling and cardiac myofibril disorganization in late-stage mice

increased heart weight ( J:244948 )

• adult heart weight to body weight (HW/BW) ratios and heart weight to tibia length (HW/TL) ratios are significantly higher than in wild-type controls

cardiac hypertrophy ( J:244948 )

• adult hearts show a significant increase in the mRNA expression of the hypertrophic markers atrial natriuretic factor (Nppa/Anf) and B-type natriuretic peptide (Nppb/Bnp)

cardiac fibrosis ( J:244948 )

• adult hearts show evidence of mild fibrosis

decreased heart left ventricle muscle contractility ( J:244948 )

• rare 6-month-old survivors show cardiac dysfunction with a significant decrease in fractional shortening (FS)

abnormal fetal cardiomyocyte physiology ( J:244948 )

• isolated mouse neonatal cardiomyocytes (MNCs) show a significant reduction in cell viability and mitochondrial membrane potential along with a significant increase in mitochondrial [Ca2+] and elevated ROS levels relative to wild-type cells

abnormal heart echocardiography feature ( J:244948 )

• M-mode echocardiography shows a significant increase in left ventricular end-diastolic diameter (LVEDD) and reduced fractional shortening (FS) in rare 6-month-old survivors

cellular

abnormal myocardial fiber mitochondrial morphology ( J:244948 )

• EM analysis of heart sections shows mitochondrial membrane rupture and a significant increase in mitochondrial size in late-stage mice

increased mitochondrial size ( J:244948 )

• EM analysis of heart sections shows a significant increase in mitochondrial size in late-stage mice

increased cardiomyocyte apoptosis ( J:244948 )

• 6-mo-old hearts show a significant increase in cytochrome c and caspase-3 protein expression levels

increased endoplasmic reticulum stress ( J:244948 )

• 6-mo-old hearts and neonatal P1 heart tissues show a significant increase in the expression of nearly all ER stress response genes tested

• moreover, 6-mo-old hearts show a significant increase in several ER stress response proteins (GRp78, GRp94, peIF2, and CHOP)

abnormal mitochondrial physiology ( J:244948 )

• MNCs show a significant reduction in mitochondrial membrane potential along with an increase in mitochondrial [Ca2+] relative to wild-type cells

oxidative stress ( J:244948 )

• tunicamycin-treated MNCs show significantly higher reactive oxygen species (ROS) levels than similarly treated wild-type cells

homeostasis/metabolism

abnormal calcium ion homeostasis ( J:244948 )

• untreated mouse neonatal cardiomyocytes (MNCs) show reduced spontaneous Ca2+ frequency and enhanced Ca2+ transient amplitude relative to wild-type MNCs, indicating a greater Ca2+ store and/or enhanced Ca2+ release from ER/SR

• MNCs treated with histamine (an IP3R agonist) show a significantly higher Ca2+ transient amplitude than histamine-treated wild-type MNCs

• MNCs treated with 2-aminoethoxydiphenyl borate (2-APB; an IP3R inhibitor) also show a significantly higher Ca2+ transient amplitude than 2-APB-treated wild-type MNCs

nervous system

encephalomeningocele ( J:244948 )

• at E12.5, 60% (3 of 5) dead embryos exhibit a phenotype resembling encephalocele

muscle

abnormal myocardial fiber mitochondrial morphology ( J:244948 )

• EM analysis of heart sections shows mitochondrial membrane rupture and a significant increase in mitochondrial size in late-stage mice

increased myocardial fiber size ( J:244948 )

• wheat germ agglutinin (WGA) staining of adult hearts shows a significant increase in cardiac cell area relative to wild-type hearts

myocardial fiber disarray ( J:244948 )

• EM analysis of heart sections shows significant myocyte swelling and cardiac myofibril disorganization in late-stage mice

decreased heart left ventricle muscle contractility ( J:244948 )

• rare 6-month-old survivors show cardiac dysfunction with a significant decrease in fractional shortening (FS)

increased cardiomyocyte apoptosis ( J:244948 )

• 6-mo-old hearts show a significant increase in cytochrome c and caspase-3 protein expression levels

Genotype
MGI:7493377

ht2

• Allelic Composition: Erp44^Gt(XB599)Byg/Erp44⁺
• Genetic Background: B6.129P2(129S)-Erp44^Gt(XB599)Byg

mortality/aging

abnormal susceptibility to injury induced morbidity/mortality ( J:244948 )

♂ • aortic-banded mice exhibit a significantly lower survival rate than aortic-banded wild-type controls at 60 days post-surgery; increased mortality induced by banding is evident within 24 hrs post-surgery

♂ • however, no significant differences in mortality are seen under sham surgery conditions

premature death ( J:244948 )

• mice exhibit significantly decreased survival between 6 and 15 months of age

cardiovascular system

abnormal myocardial fiber mitochondrial morphology ( J:244948 )

♂ • at 2 weeks after aortic banding surgery, cardiomyocyte mitochondria exhibit swelling, degeneration of the mitochondrial matrix, poorly developed cristae and electron-dense matrix deposits, as well as crystalline and amorphous inclusions and vacuolization, unlike banded wild-type controls

myocardial fiber disarray ( J:244948 )

♂ • at 2 weeks after aortic banding surgery, mice exhibit cardiac myofibril disorganization, unlike banded wild-type controls

abnormal fetal cardiomyocyte physiology ( J:244948 )

• isolated mouse neonatal cardiomyocytes (MNCs) show a significant increase in mitochondrial [Ca2+] and ROS levels relative to wild-type cells

increased myocardial fiber apoptosis ( J:244948 )

♂ • after aortic banding surgery, heart sections show a significant increase in the number of TUNEL+ cells and cleaved caspase-12, -9, and -3 levels than banded wild-type hearts

increased response of heart to induced stress ( J:244948 )

♂ • at 2 weeks after aortic banding surgery, surviving mice show marked upregulation of Nppa/Anf mRNA expression, significantly increased HW/BW and HW/TL ratios, cardiac cell hypertrophy and collagen expression, aberrant myocardial ultrastructure with abnormal mitochondria morphology and myofibril disorganization, increased interventricular septum thickness, increased LV posterior wall diameter, LV end-systolic diameter and LV end-diastolic diameter, decreased fractional shortening (FS) and heart rate, and enhanced activation of ER stress response genes and apoptotic cell death relative to aortic-banded wild-type controls

cellular

abnormal myocardial fiber mitochondrial morphology ( J:244948 )

♂ • at 2 weeks after aortic banding surgery, cardiomyocyte mitochondria exhibit swelling, degeneration of the mitochondrial matrix, poorly developed cristae and electron-dense matrix deposits, as well as crystalline and amorphous inclusions and vacuolization, unlike banded wild-type controls

increased myocardial fiber apoptosis ( J:244948 )

♂ • after aortic banding surgery, heart sections show a significant increase in the number of TUNEL+ cells and cleaved caspase-12, -9, and -3 levels than banded wild-type hearts

abnormal mitochondrial crista morphology ( J:244948 )

♂ • at 2 weeks after aortic banding surgery, cardiomyocyte mitochondria show poorly developed cristae, unlike banded wild-type controls

abnormal mitochondrial matrix morphology ( J:244948 )

♂ • at 2 weeks after aortic banding surgery, cardiomyocyte mitochondria exhibit degeneration of the mitochondrial matrix and electron-dense matrix deposits, unlike banded wild-type controls

dilated mitochondrion ( J:244948 )

♂ • at 2 weeks after aortic banding surgery, cardiomyocyte mitochondria exhibit swelling, unlike banded wild-type controls

increased endoplasmic reticulum stress ( J:244948 )

♂ • at 2 weeks after aortic banding surgery, hearts exhibit significantly higher expression of several ER stress response genes than banded wild-type hearts

abnormal mitochondrial physiology ( J:244948 )

• MNCs show a significant increase in mitochondrial [Ca2+] relative to wild-type cells

oxidative stress ( J:244948 )

• tunicamycin-treated MNCs show significantly higher reactive oxygen species (ROS) levels than similarly treated wild-type cells

homeostasis/metabolism

increased response of heart to induced stress ( J:244948 )

♂ • at 2 weeks after aortic banding surgery, surviving mice show marked upregulation of Nppa/Anf mRNA expression, significantly increased HW/BW and HW/TL ratios, cardiac cell hypertrophy and collagen expression, aberrant myocardial ultrastructure with abnormal mitochondria morphology and myofibril disorganization, increased interventricular septum thickness, increased LV posterior wall diameter, LV end-systolic diameter and LV end-diastolic diameter, decreased fractional shortening (FS) and heart rate, and enhanced activation of ER stress response genes and apoptotic cell death relative to aortic-banded wild-type controls

abnormal calcium ion homeostasis ( J:244948 )

• untreated mouse neonatal cardiomyocytes (MNCs) show reduced spontaneous Ca2+ frequency and enhanced Ca2+ transient amplitude relative to wild-type MNCs, indicating a greater Ca2+ store and/or enhanced Ca2+ release from ER/SR

• MNCs treated with histamine (an IP3R agonist) show a significantly higher Ca2+ transient amplitude than histamine-treated wild-type MNCs

• MNCs treated with 2-aminoethoxydiphenyl borate (2-APB; an IP3R inhibitor) also show a significantly higher Ca2+ transient amplitude than 2-APB-treated wild-type MNCs

• however, overexpression of ERP44 by lentivirus infection restores the Ca2+ transient amplitude and frequencies to wild-type levels

abnormal susceptibility to injury induced morbidity/mortality ( J:244948 )

♂ • aortic-banded mice exhibit a significantly lower survival rate than aortic-banded wild-type controls at 60 days post-surgery; increased mortality induced by banding is evident within 24 hrs post-surgery

♂ • however, no significant differences in mortality are seen under sham surgery conditions

muscle

abnormal myocardial fiber mitochondrial morphology ( J:244948 )

♂ • at 2 weeks after aortic banding surgery, cardiomyocyte mitochondria exhibit swelling, degeneration of the mitochondrial matrix, poorly developed cristae and electron-dense matrix deposits, as well as crystalline and amorphous inclusions and vacuolization, unlike banded wild-type controls

myocardial fiber disarray ( J:244948 )

♂ • at 2 weeks after aortic banding surgery, mice exhibit cardiac myofibril disorganization, unlike banded wild-type controls

increased myocardial fiber apoptosis ( J:244948 )

♂ • after aortic banding surgery, heart sections show a significant increase in the number of TUNEL+ cells and cleaved caspase-12, -9, and -3 levels than banded wild-type hearts