Phenotypes associated with this allele

• Allele Symbol: Eif2ak3^tm1Dron
• Allele Name: targeted mutation 1, David Ron
• Allele ID: MGI:2177666
• Summary: 6 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Eif2ak3^tm1Dron/Eif2ak3^tm1Dron	129S6/SvEvTac-Eif2ak3^tm1Dron	MGI:3582644
hm2	Eif2ak3^tm1Dron/Eif2ak3^tm1Dron	involves: 129S6/SvEvTac	MGI:3723590
hm3	Eif2ak3^tm1Dron/Eif2ak3^tm1Dron	involves: 129S6/SvEvTac * Swiss Webster	MGI:3582643
ht4	Eif2ak3^tm1Dron/Eif2ak3^+	either: 129S6/SvEvTac-Eif2ak3^tm1Dron or (involves: 129S6/SvEvTac * C57BL/6)	MGI:3582645
cx5	Eif2ak3^tm1Dron/Eif2ak3^tm1Dron Tg(GFAP-tTA)110Pop/0 Tg(tetO-Ifng)184Pop/0	involves: 129S6/SvEvTac * C57BL/6 * DBA/2 * Swiss Webster	MGI:4355948
cx6	Eif2ak3^tm1Dron/Eif2ak3^+ Tg(GFAP-tTA)110Pop/0 Tg(tetO-Ifng)184Pop/0	involves: 129S6/SvEvTac * C57BL/6 * DBA/2 * Swiss Webster	MGI:4355950

Genotype
MGI:3582644

hm1

• Allelic Composition: Eif2ak3^tm1Dron/Eif2ak3^tm1Dron
• Genetic Background: 129S6/SvEvTac-Eif2ak3^tm1Dron

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

mortality/aging

postnatal lethality, complete penetrance ( J:70005 )

• died in the first few days of life

Genotype
MGI:3723590

hm2

• Allelic Composition: Eif2ak3^tm1Dron/Eif2ak3^tm1Dron
• Genetic Background: involves: 129S6/SvEvTac

cellular

abnormal cell physiology ( J:124971 )

• expression of unfolded protein response target genes (Hspa5, Ddit3, Edem, Dnajc3a, Wars, Ero1lb and Pdia4) is decreased in mouse embryonic fibroblasts stressed with tunicamycin or thapsigargin results

• mouse embryonic fibroblast cells are profoundly deficient in their recovery from dithiothreitol realtive to wild-type cells

homeostasis/metabolism

increased physiological sensitivity to xenobiotic ( J:124971 )

• mouse embryonic fibroblast cells are profoundly deficient in their recovery from dithiothreitol

Genotype
MGI:3582643

hm3

• Allelic Composition: Eif2ak3^tm1Dron/Eif2ak3^tm1Dron
• Genetic Background: involves: 129S6/SvEvTac * Swiss Webster

mortality/aging

postnatal lethality ( J:70005 )

• about half the expected number of homozygous mice were recovered at weaning

growth/size/body

decreased body weight ( J:70005 )

postnatal growth retardation ( J:70005 )

homeostasis/metabolism

steatorrhea ( J:70005 )

• resulted from pancreatic maldigestion

hyperglycemia ( J:70005 )

• seen after 4 weeks of age, primarily due to the failure of the endocrine pancreas to secrete adequate amounts of insulin

decreased circulating insulin level ( J:70005 )

digestive/alimentary system

abnormal exocrine pancreas morphology ( J:70005 )

• increased cell death in the exocrine pancreas

• the endoplasmic reticulum (ER) in the exocrine pancreas was segmented instead of organized into long, thin, densely packed cisterna and its lumen was distended with material of higher electron density than the contents of wildtype ER

steatorrhea ( J:70005 )

• resulted from pancreatic maldigestion

exocrine pancreatic insufficiency ( J:70005 )

• observed in most homozygotes by 6-8 weeks of age

endocrine/exocrine glands

abnormal exocrine pancreas morphology ( J:70005 )

• increased cell death in the exocrine pancreas

• the endoplasmic reticulum (ER) in the exocrine pancreas was segmented instead of organized into long, thin, densely packed cisterna and its lumen was distended with material of higher electron density than the contents of wildtype ER

abnormal pancreatic islet morphology ( J:70005 )

• observed occasional cells with striking, abundant, and dilated membrane-bounded cisterna filled with a dense content and these cells generally had fewer secretory granules

• with time, size of islets decreased

increased pancreatic alpha cell number ( J:70005 )

• with time, proportion of glucagon-positive cells increased and they were found to populate the core of the islet as well as its mantle

decreased pancreatic beta cell number ( J:70005 )

• with time, the mass of insulin-producing cells diminished

abnormal pancreas physiology ( J:70005 )

• increased levels of endoplasmic reticulum stress in the pancreas

exocrine pancreatic insufficiency ( J:70005 )

• observed in most homozygotes by 6-8 weeks of age

abnormal pancreatic beta cell physiology ( J:70005 )

• increased glucose-induced proinsulin biosynthesis in islets of Langerhans, however processing of proinsulin was normal

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Wolcott-Rallison syndrome		DOID:0090060	OMIM:226980	J:70005

Genotype
MGI:3582645

ht4

• Allelic Composition: Eif2ak3^tm1Dron/Eif2ak3⁺
• Genetic Background: either: 129S6/SvEvTac-Eif2ak3^tm1Dron or (involves: 129S6/SvEvTac * C57BL/6)

homeostasis/metabolism

impaired glucose tolerance ( J:70005 )

• reduced ability to clear glucose following an intraperitoneal glucose injection, however weight and longevity were normal

Genotype
MGI:4355948

cx5

• Allelic Composition: Eif2ak3^tm1Dron/Eif2ak3^tm1Dron; Tg(GFAP-tTA)110Pop/0; Tg(tetO-Ifng)184Pop/0
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6 * DBA/2 * Swiss Webster

mortality/aging

postnatal lethality, complete penetrance ( J:99655 )

• pups die around P12 regardless whether dams received doxycycline to the end of gestation or until E14

Genotype
MGI:4355950

cx6

• Allelic Composition: Eif2ak3^tm1Dron/Eif2ak3⁺; Tg(GFAP-tTA)110Pop/0; Tg(tetO-Ifng)184Pop/0
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6 * DBA/2 * Swiss Webster

mortality/aging

premature death ( J:99655 )

• greater than 90% of animals die by postnatal day 27

growth/size/body

postnatal growth retardation ( J:99655 )

• pups are significantly smaller than controls littermates when doxycycline treatment is stopped on E14

nervous system

tonic seizures ( J:99655 )

• >60% of animals display tonic seizures

abnormal oligodendrocyte apoptosis ( J:99655 )

• in cervical spinal cord at P14, number of apoptotic oligodendrocytes is significantly greater than in controls when doxycycline treatment is stopped at E14

increased spinal cord apoptosis ( J:99655 )

• in cervical spinal cord at P14, number of apoptotic oligodendrocytes is significantly greater than in controls when doxycycline treatment is stopped at E14

abnormal oligodendrocyte morphology ( J:99655 )

• when doxycycline treatment is stopped at E14, very few oligodendrocytes are detected in corpus callosum and cerebellum at P14

• if mice are treated with doxycycline until they reach maturity (4 weeks) and then are released from doxycycline, oligodendrocyte survival is unaffected

abnormal spinal cord white matter morphology ( J:99655 )

• >80% of axons are unmyelinated compared to 30% of spinal cord axons in double mutants on a wild-type Eif2ak3 background when doxycycline treatment is stopped at E14; in mice continuously receiving doxycycline treatment, <10% of spinal cord axons are unmyelinated

• if mice are treated with doxycycline until they reach maturity (4 weeks) and then are released from doxycycline, normal myelin is observed in the central nervous system

abnormal myelination ( J:99655 )

• level of myelin in CNS is significantly reduced at P14 compared to double transgenic mice with wild-type Eif2ak3

behavior/neurological

tremors ( J:99655 )

• severe tremors are observed

tonic seizures ( J:99655 )

• >60% of animals display tonic seizures

cellular

abnormal oligodendrocyte apoptosis ( J:99655 )

• in cervical spinal cord at P14, number of apoptotic oligodendrocytes is significantly greater than in controls when doxycycline treatment is stopped at E14

increased spinal cord apoptosis ( J:99655 )

• in cervical spinal cord at P14, number of apoptotic oligodendrocytes is significantly greater than in controls when doxycycline treatment is stopped at E14