Phenotypes Associated with This Genotype

Genotype
MGI:3715869

• Allelic Composition: Slc25a12^{Gt(OST123999)Lex}/Slc25a12^{Gt(OST123999)Lex}
• Genetic Background: involves: 129S5/SvEvBrd * C57BL/6

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

mortality/aging

postnatal lethality, complete penetrance ( J:101164 , J:243212 )

• many die between E18 and P15 with almost none surviving beyond 22 days (J:101164)

homeostasis/metabolism

decreased gamma-aminobutyric acid level ( J:193095 )

• striatal GABA is reduced to 60% of wild-type levels

increased taurine level ( J:243212 )

• taurine levels are increased in the brain

abnormal dopamine level ( J:193095 )

• striatum shows a reduction in dopamine (to 64%) and its metabolites, 3-MT (to 43%) and HVA (to 68%)

• however, DOPAC content in the striatum is normal, resulting in increased DOPAC/dopamine ratio

• the limbic system shows a reduction in dopamine (57%) and DOPAC (50%), but only a nonsignificant decrease in HVA

• these results suggest impaired dopamine release and increased intraneuronal metabolism of dopamine in the striatum

decreased serotonin level ( J:193095 )

• decrease in 5-HT levels and its intracellular degradation product 5-HIAA in diencephalon and brainstem

nervous system

abnormal brain morphology ( J:101164 , J:193095 , J:243212 )

• N-acetylaspartate brain content is at 36 and 29% of wild type values at P10 and P20, respectively (J:101164)

• N-acetylaspartylglutamate brain levels remain at about 60 and 80% of wild type at P10 and P20, respectively (J:101164)

• aspartate concentration in the brain is about 11 and 6% of wild type at P10 and P20, respectively (J:101164)

• decrease in whole brain glutamine content which is more prominent in the straitum (29% of wild-type levels) (J:193095)

• however, brain aspartate, serine and alanine levels are normal and noradrenaline content is normal (J:193095)

• P17 mice show a decrease in N-acetylaspartate levels in the brain, with decreases seen in the cortex gray matter, the frontal white matter, and brainstem regions (J:243212)

• taurine levels are increased in the brain (J:243212)

• however, lactate levels in the brain of P17 mice are similar to wild-type mice (J:243212)

enlarged lateral ventricles ( J:101164 , J:193095 )

decreased striatum size ( J:193095 )

• reduction in size of the striatum, with the striatum/brain ratio size reduced to 80%

abnormal GABAergic neuron morphology ( J:193095 )

• marker analysis indicates a deficiency in maturation of medium spiny GABA neurons in the striatum

abnormal nervous system physiology ( J:193095 )

• monoamine metabolism is impaired in the brain, with increased intraneuronal metabolism of dopamine in the striatum but not the limbic system

convulsive seizures ( J:101164 )

• develop by day 19 to 21

abnormal myelination ( J:101164 )

• at day 18 to 20, hypomyelination occurs in the central nervous system, such as in the corpus callosum, white matter of the cerebral cortex, anterior commissure, internal capsule, and pyramidal tract

• myelin-specific protein levels are decreased at 20 days

abnormal synaptic dopamine release ( J:193095 )

• the increased DOPAC/dopamine ratio suggest impaired dopamine release

behavior/neurological

increased anxiety-related response ( J:193095 )

• in the aversive (lighted) condition of the open field, mice travel less distance in periphery, indicating increased anxiety

increased thigmotaxis ( J:193095 )

• mice exhibit increased thigmotaxic behavior in darkness in the open field, indicating increased anxiety

limb grasping ( J:193095 )

• mice show a limb clasping phenotype instead of a normal escape posture

tremors ( J:101164 )

• occur after day 16

impaired balance ( J:193095 )

• on the balance beam, mice tend to lock in a fixed spastic posture while on the beam and almost all fall off the bar

impaired coordination ( J:101164 )

• after day 14 mice display impaired coordination in a hanging wire test

impaired limb coordination ( J:193095 )

• mice show a lack of motor coordination in the hindlimbs

hunched posture ( J:101164 )

• develop by day 19 to 21

abnormal gait ( J:193095 )

• mice exhibit a shorter stride length and hindpaw base width and an erratic direction of path and incoordination

increased vertical activity ( J:193095 )

• vertical activity tends to be higher in the darkness condition

increased locomotor activity ( J:193095 )

• total distance traveled in darkness in the open field is increased

• mice are as fast as wild-type mice but have a lower resting time, indicating hyperactivity

• in the aversive (lighted) condition of the open field, mice show a burst of speed in the center of the arena, indicating hyperactivity

hyperresponsive ( J:193095 )

• mice exhibit hyper-reactivity in the toe pinch test and an exacerbated response to a finger stroke in the touch escape test

• however, no alterations in other sensory function in visual placing, blast response, tactile and vibrissae orientation, are seen

convulsive seizures ( J:101164 )

• develop by day 19 to 21

growth/size/body

decreased body weight ( J:101164 )

• when mice die they are 22% of the weight of a wild-type mouse

• weights of several organs (including liver, kidney, heart, brain, thymus, lung, spleen, stomach, and bone and skeletal muscle) are decreased

postnatal growth retardation ( J:101164 )

cellular

abnormal cellular respiration ( J:243212 )

• cell respiration is deceased in neurons but not in astrocytes

• however, neurons and astrocytes show normal glucose consumption and lactate production

abnormal aerobic respiration ( J:101164 )

• respiration rate with glutamate plus malate in skeletal muscle is reduced to about 50% of that in wild type, but observe no differences when using pyruvate and malate

• malate-aspartate shuttle (MAS) activity in skeletal muscle and brain mitochondria is very low

• aspertate formation from glutamate and malate by isolated brain mitochondria is reduced

oxidative stress ( J:193095 )

• increase in oxidative stress in the striatum as shown by a decreased GSH/GSSG ratio

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
developmental and epileptic encephalopathy 39		DOID:0080349	OMIM:612949	J:243212