Phenotypes Associated with This Genotype

Genotype
MGI:5829465

• Allelic Composition: Slc7a5^tm1.1Daca/Slc7a5^tm1.1Daca; Tg(Tek-cre)12Flv/0
• Genetic Background: B6J.Cg-Slc7a5^tm1.1Daca Tg(Tek-cre)12Flv

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

homeostasis/metabolism

abnormal translation ( J:238065 )

• polysome profiling of brain cortical lysates showed a significant shift of ribosomes from actively translating polysomes toward the monosomal fraction, indicating decreased mRNA translation initiation in the brain

abnormal amino acid level ( J:238065 )

• after birth (P2-P14) and in adult stages (>P40), brain levels of branched-chain amino acids (BCAAs), esp. leucine and isoleucine, are abnormally low while levels of a few other amino acids (e.g., histidine, serine, and phenylalanine) are increased relative to those in age-matched controls

• brain histidine levels are several fold higher than in control mice

• brain levels of leucine and isoleucine are normalized after 3 weeks of intracerebroventricular (i.c.v.) BCAA (leucine and isoleucine) delivery

• brain levels of several other large neutral amino acids (LNAAs) including tyrosine and tryptophan are relatively normal, and serum amino acid levels are unchanged

• no major changes in brain LNAA and BCAA levels are noted at E14.5

increased phenylalanine level ( J:238065 )

• brain levels of phenylalanine are increased

increased serine level ( J:238065 )

• brain serine levels are modestly but significantly increased

abnormal amino acid metabolism ( J:238065 )

• mice show abnormal activation of the amino acid response (AAR) signal transduction pathway in the brain

behavior/neurological

abnormal behavior ( J:238065 )

• at P55-P65, mice exhibit motor delay and autism-like phenotypes

• some neurobehavioral phenotypes can be rescued by i.c.v. administration of leucine and isoleucine in adulthood

• mice do not show excessive grooming or stereotyped behavior in the marble burying test

limb grasping ( J:238065 )

• 89% of mice display hind limb clasping

• fewer mice (50%) show clasping after 3 weeks of i.c.v. BCAA delivery

impaired coordination ( J:238065 )

• mice show increased latency to cross the beam in the walking beam test

abnormal gait ( J:238065 )

• in the footprint test, mice show decreased stride and stance length and increased sway length relative to controls

• gait is improved after 3 weeks of i.c.v. BCAA delivery with complete normalization of the sway length

short stride length ( J:238065 )

decreased vertical activity ( J:238065 )

• rearing is significantly reduced

• number of rearings is normalized after 3 weeks of i.c.v. BCAA delivery

decreased locomotor activity ( J:238065 )

• mice show reduced explorative behavior and lower velocity in an open field test

• open field activity is normalized after 3 weeks of i.c.v. BCAA delivery

abnormal social investigation ( J:238065 )

• in the three chamber sociability test, P55-P65 mice fail to show preference for an unfamiliar caged wild-type mouse over a caged object, unlike controls

• in the juvenile social interaction test, P25-P35 mice tend to stay farther apart from their cage mate and show fewer nose-to-nose contacts than controls

excessive vocalization ( J:238065 )

• in the isolation-induced ultrasonic vocalization test, pups separated from the mother emit an increased number of calls starting at P8

motor developmental delay ( J:238065 )

• at P55-P65, mice exhibit motor delay

skeleton

kyphosis ( J:238065 )

• 44% of mice display kyphosis

• fewer mice (25%) show kyphosis after 3 weeks of i.c.v. BCAA delivery

nervous system

nervous system phenotype ( J:238065 )

N • brain neurotransmitter levels (dopamine, serotonin, histamine) are normal

abnormal synaptic bouton morphology ( J:238065 )

• EM imaging of somatosensory cortex layers 2-3 revealed a decreased area of GABAergic boutons and decreased density of vesicles per bouton

abnormal inhibitory synapse morphology ( J:238065 )

• the intensity of vesicular GABA transporter (VGAT) staining, a marker for GABAergic presynaptic terminals, is reduced in the somatosensory cortex

• however, protein levels the GABAergic postsynaptic marker neuroligin 2 are normal

abnormal symmetric synapse morphology ( J:238065 )

• mice show a significant reduction of vesicle number in symmetric synapses in the somatosensory cortex

abnormal synaptic vesicle number ( J:238065 )

• mice show a significant reduction of vesicle number in symmetric synapses in the somatosensory cortex

abnormal CNS synaptic transmission ( J:238065 )

• mice exhibit a significant cortical excitation and inhibition imbalance

abnormal miniature excitatory postsynaptic currents ( J:238065 )

• mice show a slight increase in the amplitude of mEPSCs in somatosensory cortex layers 2-3 pyramidal neurons

decreased miniature inhibitory postsynaptic current frequency ( J:238065 )

• mice show a marked reduction in the frequency of mIPSCs in somatosensory cortex layers 2-3 pyramidal neurons as well as in cerebellar Purkinje cells

cellular

abnormal translation ( J:238065 )

• polysome profiling of brain cortical lysates showed a significant shift of ribosomes from actively translating polysomes toward the monosomal fraction, indicating decreased mRNA translation initiation in the brain

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
autism spectrum disorder		DOID:0060041		J:238065