Phenotypes Associated with This Genotype

Genotype
MGI:4818648

• Allelic Composition: Ndufs4^tm1Rpa/Ndufs4^tm1Rpa; Tg(Nes-cre)1Kln/0
• Genetic Background: involves: 129S4/SvJaeSor * C57BL/6 * SJL

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

mortality/aging

premature death ( J:161393 )

• mice die between P35 and P50

nervous system

seizures ( J:161393 )

• seizures increase as disease progresses

environmentally induced seizures ( J:161393 )

• in some mice when handled

tonic-clonic seizures ( J:161393 )

• in some mice

abnormal brain vasculature morphology ( J:161393 )

• vasculature in the vestibular nuclei and posterior cerebellum is increased compared to in wild-type mice

intracranial hemorrhage ( J:161393 )

• at late stages, mice exhibit hemorrhages in the brainstem and occasionally the midbrain unlike in wild-type mice

• mice exhibit a higher frequency of hemorrhage in the midbrain, and of gliosis and spongiform lesions in the anterior cerebellum compared with Ndufs4^tm1.1Rpa homozygotes

brainstem hemorrhage ( J:161393 )

• more often than in Ndufs4^tm1.1Rpa homozygotes

brain vacuoles ( J:161393 )

gliosis ( J:161393 )

• mice exhibit a higher frequency of hemorrhage in the midbrain, and of gliosis and spongiform lesions in the anterior cerebellum compared with Ndufs4^tm1.1Rpa homozygotes

microgliosis ( J:161393 )

astrocytosis ( J:161393 )

optic nerve atrophy ( J:161393 )

• in some mice

spongiform encephalopathy ( J:161393 )

• after P38, mice exhibit spongiform encephalpathy within the vestibular nuclei of the brainstem, inferior olive, fastigial nucleus, caudal cerebellar vermis (nodulus and uvula), and olfactory bulb unlike wild-type mice

• mice exhibit a higher frequency of hemorrhage in the midbrain, and of gliosis and spongiform lesions in the anterior cerebellum compared with Ndufs4^tm1.1Rpa homozygotes

behavior/neurological

lethargy ( J:161393 )

• after P21

abnormal emotion/affect behavior ( J:161393 )

• mice are very submissive and rarely vocalize in response to stress unlike wild-type mice

decreased aggression ( J:161393 )

• mice are docile and not easily provoked compared with wild-type mice

decreased grooming behavior ( J:161393 )

• at late stages, mice groom and scratch rarely unlike wild-type mice

tremors ( J:161393 )

• intermittent

abnormal motor coordination/balance ( J:161393 )

ataxia ( J:161393 )

• starting at P35, mice develop severe ataxia with splayed legs and become unresponsive to a firm nudge unlike wild-type mice

• ataxia worsens between P35 and P50

impaired balance ( J:161393 )

• after P21, mice exhibit deteriorating performance on a balance beam compared with wild-type mice

• starting at P35, mice become unstable, lose their balance, and fall over unlike wild-type mice

• mice are unable to maintain their balance after P40 unlike wild-type mice

impaired coordination ( J:161393 )

• after P21, mice exhibit deteriorating performance on a balance beam compared with wild-type mice

• after P40, mice exhibit deteriorating performance on a rotarod compared with wild-type mice

impaired swimming ( J:161393 )

• in a forced swim test after P21, some mice stall, corkscrew, swim upright, or swim poorly compared with wild-type mice

abnormal posture ( J:161393 )

• mice are sometime prone or unable to remain in a sitting position unlike wild-type mice

trunk curl ( J:161393 )

straub tail ( J:161393 )

• in some mice

tail dragging ( J:161393 )

• in some mice

abnormal gait ( J:161393 )

• after P21, mice exhibit lop-headed, kyphosis, splayed hindlimbs, retropulsion, circling, falling, and difficulty righting unlike wild-type mice

• mice exhibit a progressive deterioration of footprint gait compared with wild-type mice

decreased locomotor activity ( J:161393 )

• mice exhibit reduced nocturnal activity compared with wild-type mice

positive geotaxis ( J:161393 )

• after P40

retropulsion ( J:161393 )

circling ( J:161393 )

abnormal sensory capabilities/reflexes/nociception ( J:161393 )

impaired righting response ( J:161393 )

• slow and awkward starting at P35

hyporesponsive to tactile stimuli ( J:161393 )

• mice are less responsive to handling, touch, and toe pinch than wild-type mice

decreased startle reflex ( J:161393 )

• as mice age

hyperekplexia ( J:161393 )

• in some mice

limb grasping ( J:161393 )

• after P40

abnormal nest building behavior ( J:161393 )

• after middle stage disease, mice exhibit reduced nest building behavior compared with wild-type mice

decreased vocalization ( J:161393 )

• handling, toe pinch, and other stress rarely elicits vocalization unlike similarly treated wild-type mice

seizures ( J:161393 )

• seizures increase as disease progresses

environmentally induced seizures ( J:161393 )

• in some mice when handled

tonic-clonic seizures ( J:161393 )

• in some mice

vision/eye

optic nerve atrophy ( J:161393 )

• in some mice

cataract ( J:161393 )

• in some mice

blepharoptosis ( J:161393 )

• in some mice

abnormal vision ( J:161393 )

• mice exhibit decreased visual acuity measured by Morris water maze, visual cliff test, and visual placing compared with wild-type mice

growth/size/body

decreased body size ( J:161393 )

• at P21

weight loss ( J:161393 )

• between P35 and P50

decreased body length ( J:161393 )

postnatal growth retardation ( J:161393 )

cardiovascular system

abnormal brain vasculature morphology ( J:161393 )

• vasculature in the vestibular nuclei and posterior cerebellum is increased compared to in wild-type mice

intracranial hemorrhage ( J:161393 )

• at late stages, mice exhibit hemorrhages in the brainstem and occasionally the midbrain unlike in wild-type mice

• mice exhibit a higher frequency of hemorrhage in the midbrain, and of gliosis and spongiform lesions in the anterior cerebellum compared with Ndufs4^tm1.1Rpa homozygotes

brainstem hemorrhage ( J:161393 )

• more often than in Ndufs4^tm1.1Rpa homozygotes

decreased heart rate ( J:161393 )

• measured by OxMouse

respiratory system

abnormal breathing pattern ( J:161393 )

• as early as P14, mice exhibit intermittent breathing irregularities including hypo- and hyperventilation and gasping unlike wild-type mice

respiratory distress ( J:161393 )

• intermittent as early as P14

cellular

abnormal respiratory electron transport chain ( J:161393 )

• submitochondrial particles isolated from the liver exhibit little to no complex I activity unlike wild-type samples

• complex I-dependent oxygen consumption in brain tissue is reduced compared to in wild-type mice

• however, mice exhibit normal complex II and IV activity

skeleton

kyphosis ( J:161393 )

homeostasis/metabolism

decreased body temperature ( J:161393 )

• at P30, mice exhibit decreased resting body temperature with spontaneous hypothermia unlike wild-type mice

muscle

abnormal muscle tone ( J:161393 )

• mice exhibit deficient or marked resistance/freezing in either hindlimb unlike wild-type mice

hematopoietic system

microgliosis ( J:161393 )

immune system

microgliosis ( J:161393 )

integument

integument phenotype ( J:161393 )

N • unlike Ndufs4^tm1.1Rpa homozygotes, the hair cycle is normal

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Leigh disease		DOID:3652	OMIM:256000	J:161393