Analysis Tools|
Allele Symbol Allele Name Allele ID |
Ndufs4tm1Rpa targeted mutation 1, Richard D Palmiter MGI:3527173 |
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| Summary |
6 genotypes
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• adults injected with adenoassociated virus expressing Cre-GFP to selectively inactive Ndufs4 in the vestibular nucleus exhibit increased mortality
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• adults injected with a Cre-expressing adenoassociated virus exhibit weight loss
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• adults injected with a Cre-expressing adenoassociated virus develop extensive microglial activation one month after injection
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• adults injected with a Cre-expressing adenoassociated virus exhibit more irregular breathing than controls and occasional gasping as behavior deteriorates
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• adults injected with a Cre-expressing adenoassociated virus exhibit a normal response to hypoxia but a blunted hypercapnic ventilator response
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• adults injected with a Cre-expressing adenoassociated virus exhibit motor coordination deficits on the rotorod
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• adults injected with a Cre-expressing adenoassociated virus develop extensive microglial activation one month after injection
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• adults injected with a Cre-expressing adenoassociated virus develop extensive microglial activation one month after injection
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• more than 90% mortality by P50
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• mutants show growth retardation and fail to thrive
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• intermittent breathing irregularities, including hypo- or hyperventilation and gasping
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• breathing rate is variable and lower in restrained mutants than in controls
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• mutants exhibit intermittent episodes of apnea and periods during which respiratory frequency is very irregular; number of apnea episodes increases with age
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• gasping-like episodes that occur more commonly under stressful conditions, such as when being handled
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• under normoxic conditions, mice at P8-P12 and those older than P30 have normal respiratory frequency, however they have higher tidal volume and minute ventilation
• in response to hypoxia, mutants show an initial augmentation of breathing, followed by a depression
• some mutants exhibit an abnormal response to excess CO2 (hypercapnia), with 6 of 13 mice failing to show the hyperventilation response seen in control mice, while the rest show an exaggerated response
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• edematous regions/lesions in the dorsal medulla (in the vestibular nucleus)
• extensive bilateral neuroinflammation in the vestibular nucleus
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• edematous regions/lesions in the external plexiform layer of the olfactory bulb
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• edematous regions/lesions in the cerebellar lobes
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• edematous regions/lesions in the deep cerebellar fastigial nucleus
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• neurons with cytoplasmic vacuoles are seen in the brain
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• microglial activation is rarely seen in respiratory centers such as the medial parabrachial nucleus, nucleus of the solitary tract or preBotzinger complex, however it is seen in late-stage mutants around serotonergic cell bodies in the medullary raphe
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• mutants develop a fatal progressive encephalopathy
• neurons with cytoplasmic vacuoles and aberrant mitochondria containing condensed cristae and microglia engorged with cytoplasmic remnants in the brain
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• mutants exhibit abnormal responses of the Botzinger complex in the ventral medulla under hypoxic conditions; the initial augmentation phase is normal but during depression, the amplitude of fictive gasping is decreased
• intracellular recordings of preBotzinger complex inspiratory neurons show that under control conditions, the depolarization in phase with the network burst is reduced in mutants and the number and frequency of action potentials per burst and firing frequency is lower
• upon transition from control to hypoxic conditions, mutants have a severe reduction of the underlying depolarization when challenged by hypoxia, the number and frequency of action potentials per burst drops dramatically compared to a mild reduction in controls
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• lower heart rate, especially in late stages of disease
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• percentage of oxygen saturation of arterial blood in late-stage mutants is often less than 99% which is not seen in controls
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• microglial activation is rarely seen in respiratory centers such as the medial parabrachial nucleus, nucleus of the solitary tract or preBotzinger complex, however it is seen in late-stage mutants around serotonergic cell bodies in the medullary raphe
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• microglial activation is rarely seen in respiratory centers such as the medial parabrachial nucleus, nucleus of the solitary tract or preBotzinger complex, however it is seen in late-stage mutants around serotonergic cell bodies in the medullary raphe
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Leigh disease | DOID:3652 |
OMIM:256000 |
J:190475 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• in some mice 7 months after tamoxifen treatment
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• 7 months after tamoxifen treatment
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• 7 months after tamoxifen treatment
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• in some mice 7 months after tamoxifen treatment
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice do not exhibit any overt behavioral abnormalities
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| N |
• mice do not exhibit any overt pathology
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice die between P35 and P50
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• in some mice when handled
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• in some mice
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• vasculature in the vestibular nuclei and posterior cerebellum is increased compared to in wild-type mice
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• 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 Ndufs4tm1.1Rpa homozygotes
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• more often than in Ndufs4tm1.1Rpa homozygotes
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• mice exhibit a higher frequency of hemorrhage in the midbrain, and of gliosis and spongiform lesions in the anterior cerebellum compared with Ndufs4tm1.1Rpa homozygotes
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• in some mice
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• 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 Ndufs4tm1.1Rpa homozygotes
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• mice are very submissive and rarely vocalize in response to stress unlike wild-type mice
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• mice are docile and not easily provoked compared with wild-type mice
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• at late stages, mice groom and scratch rarely unlike wild-type mice
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• 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
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• 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
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• 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
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• in a forced swim test after P21, some mice stall, corkscrew, swim upright, or swim poorly compared with wild-type mice
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• mice are sometime prone or unable to remain in a sitting position unlike wild-type mice
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• in some mice
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• in some mice
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• 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
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• mice exhibit reduced nocturnal activity compared with wild-type mice
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• after P40
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• slow and awkward starting at P35
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• mice are less responsive to handling, touch, and toe pinch than wild-type mice
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• as mice age
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• in some mice
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• after P40
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• after middle stage disease, mice exhibit reduced nest building behavior compared with wild-type mice
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• handling, toe pinch, and other stress rarely elicits vocalization unlike similarly treated wild-type mice
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• in some mice when handled
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• in some mice
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• in some mice
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• in some mice
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• mice exhibit decreased visual acuity measured by Morris water maze, visual cliff test, and visual placing compared with wild-type mice
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• at P21
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• between P35 and P50
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• vasculature in the vestibular nuclei and posterior cerebellum is increased compared to in wild-type mice
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• 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 Ndufs4tm1.1Rpa homozygotes
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• more often than in Ndufs4tm1.1Rpa homozygotes
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• measured by OxMouse
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• as early as P14, mice exhibit intermittent breathing irregularities including hypo- and hyperventilation and gasping unlike wild-type mice
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• intermittent as early as P14
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• 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
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• at P30, mice exhibit decreased resting body temperature with spontaneous hypothermia unlike wild-type mice
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• mice exhibit deficient or marked resistance/freezing in either hindlimb unlike wild-type mice
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| N |
• unlike Ndufs4tm1.1Rpa homozygotes, the hair cycle is normal
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Leigh disease | DOID:3652 |
OMIM:256000 |
J:161393 | |
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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last database update 11/12/2024 MGI 6.24 |
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