Phenotypes associated with this allele

• Allele Symbol: Th^tm1Rpa
• Allele Name: targeted mutation 1, Richard D Palmiter
• Allele ID: MGI:1860450
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Th^tm1Rpa/Th^tm1Rpa	involves: 129S7/SvEvBrd * C57BL/6	MGI:3623119
cx2	Dbh^tm2(Th)Rpa/Dbh^+ Th^tm1Rpa/Th^tm1Rpa	involves: 129S7/SvEvBrd	MGI:2175827
cx3	Dbh^tm2(Th)Rpa/Dbh^+ Th^tm1Rpa/Th^tm1Rpa	involves: 129S7/SvEvBrd * C57BL/6J	MGI:3654636

Genotype
MGI:3623119

hm1

• Allelic Composition: Th^tm1Rpa/Th^tm1Rpa
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6

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

mortality/aging

lethality throughout fetal growth and development, incomplete penetrance ( J:24347 )

• only 5% of homozygotes are recovered at E15.5; only 2.6% of pups born are homozygous

postnatal lethality, complete penetrance ( J:24347 )

• Background Sensitivity: only about 2.6% of homozygotes are born alive on an outbred genetic background; in contrast, no born homozygotes are identified out of 129/Sv inbred offspring

• all naturally born homozygotes (about 2.6%) die within 4 weeks, with most deaths occurring by P21

• similarly, all rescued homozygotes die within 5 weeks, with no survivors identified at P35

embryonic lethality during organogenesis, incomplete penetrance ( J:24347 )

• ~90% of homozygotes die between E11.5 and E15.5, apparently of cardiovascular failure

• treatment of pregnant females at stage E8.5 of pregnancy with 0.25 mg/ml of L-DOPA rescues ~50% of homozygotes to E17.5 or birth, whereas 1 mg/ml of L-DOPA rescues all homozygotes to birth

• treatment of pregnant females with 1 mg/ml of L-DOPA from E10.5 to E13.5, results in only partial rescue in utero, suggesting a continuous requirement for catecholamines

• treatment of pregnant females with 0.5 mg/ml of DOPS only partially rescues homozygotes to birth, suggesting a requirement for dopamine in addition to noradrenaline

cardiovascular system

blood vessel congestion ( J:24347 )

• at E12.5-E15.5, 6 of 14 homozygotes display congestion of blood in the liver and major blood vessels

liver vascular congestion ( J:24347 )

• at E12.5-E15.5 in 6 of 14 homozygotes

fetal cardiomyocyte disarray ( J:24347 )

• at E12.5, ventricular cardiomyocytes appear less organized

fetal cardiomyocyte vacuoles ( J:24347 )

• at E12.5, ventricular cardiomyocytes appear more vacuolated

abnormal heart atrium morphology ( J:24347 )

• at E12.5, homozygotes with dilated atria exhibit thinning of the atrial wall

dilated heart atrium ( J:24347 )

• at E12.5, 2 of 3 homozygotes display significantly dilated atria

decreased heart rate ( J:24347 )

• at E12.5, homozygotes display slight bradycardia relative to wild-type embryos (37.9 7.5 bpm vs 44.7 9.0 bpm, respectively)

growth/size/body

decreased body size ( J:24347 )

• all homozygotes that survive to term display normal birth weights but become severely runted by P7; similar runting in noted in rescued homozygotes

decreased body weight ( J:24347 )

• by P15, surviving homozygotes weigh ~40% of wild-type littermates

behavior/neurological

abnormal motor coordination/balance ( J:24347 )

• at P15, surviving homozygotes fail to balance on a rotating pencil or walk up an incline

weakness ( J:24347 )

• at P15, both naturally born and rescued homozygotes appear very weak

liver/biliary system

liver vascular congestion ( J:24347 )

• at E12.5-E15.5 in 6 of 14 homozygotes

Genotype
MGI:2175827

cx2

• Allelic Composition: Dbh^tm2(Th)Rpa/Dbh⁺; Th^tm1Rpa/Th^tm1Rpa
• Genetic Background: involves: 129S7/SvEvBrd

mortality/aging

premature death ( J:30404 )

• all die by 4 weeks of age

• twice daily treatment with 50 mg/kg L-dihydroxyphenylalanine (L-DOPA) starting around P15 rescues the lethality

growth/size/body

decreased body size ( J:30404 )

• at P10 - P15

decreased body weight ( J:30404 )

• at P16, body weight is 70% of control littermates

weight loss ( J:30404 )

• after P17 a negative growth rate is seen

• twice daily treatment with 50 mg/kg L-DOPA starting around P15 restores a nearly normal growth rate

behavior/neurological

adipsia ( J:30404 )

• injection with L-DOPA restores drinking behavior

aphagia ( J:30404 )

• injection with L-DOPA restores eating behavior with maximal intake during the first 2 hours after injection and cessation of eating by about 6 hours post injection

poor grooming ( J:30404 )

• at P10 - P15

hunched posture ( J:30404 )

• at P10 - P15

decreased locomotor activity ( J:30404 )

• at P10 - P15, travel only about 3m/hr compared to 23 m/hr in controls

• however at P16, reflexion, corneal, startle, righting, grasping, and placing reflexes are all similar to controls, balance is not impaired, and no tremors are seen

• within 15 minutes of injection of L-DOPA activity levels increase peaking at about 1 hour post injection and then decreasing so that by 12 hours post injection mice are hypoactive

decreased stereotypic behavior ( J:30404 )

• make about 280 stereotypical beam breaks per hour compared to about 700 per hour for controls

nervous system

decreased brain size ( J:30404 )

• brain size is reduced and neurons are slightly more compact; however, dopaminergic neuron and striatum morphology are similar to controls

abnormal nervous system physiology ( J:30404 )

• expression levels of tachykinin 1 and dynorphin are decreased in the striatum

homeostasis/metabolism

decreased dopamine level ( J:30404 )

• dopamine levels in the brain are low; however, levels of norepinephrine in the brain, heart, salivary glands, and adrenal glands are similar to controls

Genotype
MGI:3654636

cx3

• Allelic Composition: Dbh^tm2(Th)Rpa/Dbh⁺; Th^tm1Rpa/Th^tm1Rpa
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6J

mortality/aging

premature death ( J:58125 )

• can be maintained for at least 1.5 years with daily treatment of 50 mg/kg L-DOPA and feeding with breeder chow (4.35 kcal/g)

behavior/neurological

impaired behavioral response to addictive substance ( J:58125 )

• 19 hours after L-DOPA treatment a single dose of amphetamine (5mg/kg) induces a shorter increase in activity (1 hour compared to 2 hours in controls) and a second dose of amphetamine fails to alter activity unlike in controls

decreased food intake ( J:58125 )

• during the first 24 hours after L-DOPA treatment food intake is similar to controls but during the next 24 hours intake decreases to about 10% of wild-type

• food intake is proportional to L-DOPA dose up to 100 mg/kg

decreased compensatory feeding amount ( J:58125 )

• if food is with held for 3 or 6 hours after L-DOPA treatment mice compensate by consuming more food in the next 3 hours to consume about the same amount of food as when food is continually available; however no compensation if food is with held for 9 hours

• after a 30 hour fast when presented with a high sucrose, high-fat diet mice begin to consume food but cease eating sooner and consume only about 25% of the amount eaten by wild-type mice

hyporesponsive to tactile stimuli ( J:58125 )

• 1 hour after L-DOPA treatment a decrease in response in the paw pinch assay is seen

impaired coordination ( J:58125 )

• 24 or more hours after L-DOPA treatment rotarod and pole test performance are poor

hunched posture ( J:58125 )

akinesia ( J:58125 )

• 24 hours after L-DOPA treatment 1- and 4-limb akinesia is increased compared to controls

abnormal gait ( J:58125 )

• 24 or more hours after L-DOPA treatment the gait is awkward

decreased locomotor activity ( J:58125 )

• in untreated mice or by 24 hours after L-DOPA treatment

• a second small peak of activity occurs between 24 and 40 hours after treatment however overall activity is decreased compared to controls

hyperactivity ( J:58125 )

• for 6 - 9 hours after L-DOPA treatment activity level is higher than in wild-type

• treatment with L-DOPA and carbidopa induces a biphasic increase in activity that is more prolonged than when L-DOPA is given alone; however, in wild-type mice L-DOPA and carbidopa treatment induces inactivity

increased stereotypic behavior ( J:58125 )

• treatment with L-DOPA and carbidopa induces intense stereotypic behavior (licking and chewing of paws) between 1 and 5 hours after treatment, no such behavior is seen in controls

catalepsy ( J:58125 )

• 24 hours after L-DOPA treatment forelimb catalepsy is increased compared to controls