|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• about 70% of mutants survive to about 12 months of age
|
|
• about 30% of mutants die before 12 months of age
|
|
• by the second day after birth, mutants show a 15% decrease in weight compared to controls
|
|
• mutants exhibit reduced grip strength, indicating weakness
|
|
• reduced muscle mass
|
|
• average size of mutant fibers is larger than controls
|
|
• muscle fiber loss occurs after P7
|
|
• atrophic fibers are seen in proximal (triceps) and distal (gastrocnemius) muscles
• small but significant proportion of muscle fibers exhibit centrally located nuclei, suggesting an ongoing regenerative process in muscle
|
|
• in an impaired righting ability test, mutants are noticeably weaker by postnatal day 2
• impaired righting reflex gradually subsides so that by the end of the second week of life, differences between mutants and controls are no longer seen
• however mutants continue to display weakness as adults
|
|
• neonates exhibit a reduction of vGlut1 bouton numbers and their areas on motor neurons and a reduction of the total numbers of puncta in the ventral horn, indicating an aberration in the projection of proprioceptive sensory neurons onto ventral horns
|
|
• by P40, mutants exhibit an approximate 40% and 25% reduction in cervical and lumbar motor neurons, respectively
|
|
• the number of boutons juxtaposed against ChAT-positive motor neurons is reduced
• mean area of these synaptic boutons is reduced, suggesting an alteration in the synaptic coverage of the ventral horn motor neurons by Ia sensory terminals
• at the presynapse, neurofilament aggregates infiltrate nerve terminals and terminal arbors are swollen
• abnormal amounts of neurofilament protein persist in the nerve terminals of both proximal and distal muscles
• abnormal localization of synaptic vesicles in mutant terminals at P8 but no longer visible at P12
|
|
• NMJs in the triceps muscle are smaller, misshapen, and less mature than in controls or in mutant gastrocnemius muscle, indicating delayed maturation
• fragmented NMJs are seen in both triceps and gastrocnemius muscles
• at the postsynapse, more than 75% of gastrocnemial acetylcholine receptor clusters attain the normal pretzel-like conformation, but more than half of them appear fragmented and are measurably larger than in control NMJs
• acetylcholine receptor clusters of the triceps fail to attain the level of complexity as gastrocnemial muscle
|
|
• mutants exhibit severe defects of neuromuscular transmission at P8 but these defects are attenuated by P12 as disease progresses
• at P8, 100 Hz nerve stimulation of muscle is only able to produce 34% of the tension produced by direct muscle stimulation compared to 72% in controls, indicating that many junctions fail to active muscle fibers to threshold[?]
• at 100 Hz asynchronous release of calcium disappears at mutant NMJs undergoing numerous failures, suggesting there is little calcium entry into the nerve terminals during these events
• at P8, a decrease in the mean quantal content of the mutant junctions compared with controls, but at P10 and P12 mutant NJMs, the quantal content increases to control levels
|
|
• mean mEPP amplitude at mutant NMJs is 50-100% greater than at control junctions at P8, P10 and P12
• semitendinosus muscle of 3 month old mutants shows an increase in mEPP amplitude despite a decrease in input resistance, indicating that neuromuscular transmission defects persist at the NMJs of adults
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Werdnig-Hoffmann disease | DOID:13137 |
OMIM:253300 |
J:164292 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• median survival of 12 days
|
| N |
• neuromuscular junctions are similar to controls in the intercostal and triangularis sterni muscles
|
|
• decrease in cardiac autonomic innervation
|
|
• in L3-L5 spinal cord sections but not in the cervical or thoracic regions
|
|
• by P9
|
|
• end-stage mice display skipped or dropped beats
|
|
• at P9-P11
|
|
• at P9-P11
|
| N |
• ambulatory throughout life
|
|
• lateral instability of the hind limbs
|
|
• significantly improved righting response
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Werdnig-Hoffmann disease | DOID:13137 |
OMIM:253300 |
J:183080 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice do not survive past 2 days with a mean survival of 1 day
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• Background Sensitivity: double homozygotes are not found postnatally unlike when mice are on an inbred FVB/NJ background
|
|
• mice do not survive past 8 days with a mean survival of 5 days
|
|
• at P5
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• Background Sensitivity: double homozygotes are detected postnatally unlike when mice are on an inbred C57BL/6J background or on a mixed background involving predominantly 129 and C57BL/6J
|
|
• mean lifespan is 7 days
|
|
• mice preferentially lack innervation of the caudal band of the levator auris longus
|
|
• many endplates are partially occupied or vacant unlike in wild-type mice
|
|
• muscle fiber diameter is decreased in both slow- and fast-twitch muscles compared to in wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice do not survive past 17 days with a mean survival of 13 days
|
|
• at P5
|
|
• by day 10, mice experience difficulty walking and often fall while walking unlike wild-type mice
|
|
• by day 10, mice experience difficulty walking and often fall while walking unlike wild-type mice
|
|
• at P10, mice exhibit abnormal gait with fibrillation of the hindlimbs
|
|
• in the lumbar region of the spinal cord at P9
• however, spinal motor neuron numbers at P4 are normal
|
|
• at P14, many neuromuscular junctions are partially innervated or not innervated
• the diameter of neuromuscular junctions is smaller than in wild-type mice
|
|
• at P14, muscle fibers of the gastrocnemius are small due to atrophy
|
|
• at P5
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Werdnig-Hoffmann disease | DOID:13137 |
OMIM:253300 |
J:97103 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice do not survive past 16 days with a mean survival of 10 days
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• average survival of about 2 weeks
|
|
• TH staining of the heart to visualize sympathetic innervation indicates that mutants exhibit fewer major neuronal branches and they appear thinner and less distinct
|
|
• mice preferentially lack innervation of the caudal band of the levator auris longus
|
|
• many endplates are partially occupied or vacant unlike in wild-type mice
• mice exhibit both post- and pre-synaptic pathology at motor neuron endplates
|
|
• muscle fiber diameter is decreased in both slow- and fast-twitch muscles compared to in wild-type mice
|
|
• hearts appear flaccid and lack defined shape and gross attenuation of walls at P10 and P13
|
|
• echocardiography indicates that P6 mice exhibit deficiencies in blood flow out of the right ventricle at the pulmonary valve, with decreased peak velocity and peak gradient, indicating a reduction in pumping efficiency and blood flow from the right ventricle to the lungs
|
|
• as mice near end of life, they display a large increase in heart rate variability, ultimately displaying adjacent RR intervals that are highly inconsistent
|
|
• mice present bradycardia as early as 2 days of age, before neuromuscular symptoms
• bradyarrhythmia is characterized by progressive heart block and reduced ventricular depolarization efficiency
|
|
• at P4, mice have a first-degree heart block characterized by elongated PR interval durations
• at P10, sharp increase in the PR interval and breakdown of cardiac rhythm as mutants exhibit progressive heart block
|
|
• elongation of the time of ventricular depolarization through an increase in QRS interval duration beginning at P4
|
|
• begin to lose weight at around P10
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Werdnig-Hoffmann disease | DOID:13137 |
OMIM:253300 |
J:164446 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mean lifespan is 13 days
|
|
• mutants exhibit an increase in cardiac fibrosis compared to unaffected wild-type controls
|
|
• mutants exhibit an increase in cardiac fibrosis compared to unaffected wild-type controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• median survival is 7 days
|
|
• significant decrease in the number of fully innervated motor endplates and increase in the number of partially innervated and denervated endplates in the intercostal muscle
• however, innervation of the endplates in the triangularis sterni muscle is similar to controls
|
|
• increase in intercostal muscle homogeneous motor endplates and decrease in the number of endplates containing secondary structure
• however, endplates in the triangularis sterni muscle are similar to controls
• decrease in the number of glutamatergic excitatory synapses at P5 in the L2-L5 region of the spinal cord
|
|
• decrease in the number of glutamatergic excitatory synapses at P5 in the L2-L5 region of the spinal cord
• significant loss in average MNs per ventral horn is seen in cervical, thoracic, and lumbar spinal cords
|
|
• significant loss in average MNs per ventral horn is seen in cervical, thoracic, and lumbar spinal cords
|
|
• signs of neurodegeneration in the intercostal muscle
|
|
• threshold voltage in motor neurons is significantly lower and amplitude of the persistent inward current is significantly larger indicating increased excitability in cultured motor neurons
• high frequency of postsynaptic potentials in cultured motor neurons
|
|
• by P3 and declines over time
|
|
• at P3-P7
|
|
• at P3-P7
|
|
• at P3-P7
|
|
• decreased motor function
|
|
• never develop the ability to right when placed on the back
|
|
• at P2 or later
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Werdnig-Hoffmann disease | DOID:13137 |
OMIM:253300 |
J:183080 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• viable and indistinguishable from control littermates
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• Background Sensitivity: double homozygotes are not found postnatally unlike when mice are on an inbred FVB/NJ background
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mean lifespan is 34 days, with mutants living longer than double homozygous Smn1tm1Msd and Tg(SMN2)89Ahmb control mice
• nearly 25% of mutants live beyond 40 days, with several living beyond P70
|
|
• smaller size compared to wild-type controls at P12, although weight is greater than in double homozygous Smn1tm1Msd and Tg(SMN2)89Ahmb control mice and some mutants eventually reach the weight of unaffected mice
|
| N |
• mutants are more agile and generally fitter than double homozygous Smn1tm1Msd and Tg(SMN2)89Ahmb control mice
|
|
• 20-70% of mutants at P5-15 are able to right themselves compared to 100% of unaffected control mice (mice homozygous for Tg(SMN2)89Ahmb and heterozygous for Smn1tm1Msd)
• starting at P5, mutants show increased ability to right compared to triple transgenics homozygous for Smn1tm1Msd and Tg(SMN2)89Ahmb and hemizygous for Tg(SMN2*delta7)4299Ahmb (20-70% vs. 3-15% in the controls)
|
|
• mutants stay on the rotorod for shorter periods of time than unaffected controls (mice homozygous for Tg(SMN2)89Ahmb and heterozygous for Smn1tm1Msd)
|
|
• mutants show a slight decrease in grip strength compared to unaffected controls (mice homozygous for Tg(SMN2)89Ahmb and heterozygous for Smn1tm1Msd)
|
|
• skeletal muscle fibers are smaller than in wild-type controls, however they are larger than in triple transgenics homozygous for Smn1tm1Msd and Tg(SMN2)89Ahmb and hemizygous for Tg(SMN2*delta7)4299Ahmb
|
|
• mutants show an approximate 60% reduction of proprioceptive synapses onto motor neurons compared to triple transgenics homozygous for Smn1tm1Msd and Tg(SMN2)89Ahmb and hemizygous for Tg(SMN2*delta7)4299Ahmb
• P19 mutants show an increase in the percentage of neuromuscular junctions with perforated or fragmented endplates compared to controls homozygous for Tg(SMN2)89Ahmb, indicating a defect in synapse maturation
• mutants exhibit a modest but significant reduction in neuromuscular junction innervation in the longissimus muscle
|
|
• mutants show a slight reduction in interventricular septum thickness, although this does not reach significance
• the interventricular septum thickness is significantly improved compared to triple transgenic controls homozygous for Smn1tm1Msd and Tg(SMN2)89Ahmb and hemizygous for Tg(SMN2*delta7)4299Ahmb
|
|
• mutants exhibit a modest, but significant increase in cardiac interstitial fibrosis compared to unaffected wild-type controls
• interstitial fibrosis is significantly improved when compared to triple transgenic controls homozygous for Smn1tm1Msd and Tg(SMN2)89Ahmb and hemizygous for Tg(SMN2*delta7)4299Ahmb
|
|
• mutants start to show signs of necrosis on the ears, tails, and/or eyes at approximately P40-P50
|
|
• mutants exhibit a modest, but significant increase in cardiac interstitial fibrosis compared to unaffected wild-type controls
• interstitial fibrosis is significantly improved when compared to triple transgenic controls homozygous for Smn1tm1Msd and Tg(SMN2)89Ahmb and hemizygous for Tg(SMN2*delta7)4299Ahmb
|
|
• mutants start to show signs of necrosis on the ears, tails, and/or eyes at approximately P40-P50
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Werdnig-Hoffmann disease | DOID:13137 |
OMIM:253300 |
J:194969 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• the majority of mice were stillborn or died within 6 hours of birth
• a slightly less than expected frequency of mice with this genotype suggests that some mice may be dying in utero
• in few cases, mice of this genotype survived up to 6 days of age
|
|
• in few cases, mice of this genotype survived up to 6 days of age
|
|
• mice that survived 4-6 days displayed a decrease or lack of suckling by 48 hours postnatal
|
|
• mice that survived 4-6 days showed a marked tremor within 72-96 hours postnatal
|
|
• mice that survived 4-6 days showed a decrease in movement within 48-72 hours postnatal
|
| N |
• no musculature atrophy was detected in the quadriceps or gastrocnemius of mice that survived 4-6 days
|
|
• mice that survived 4-6 days displayed labored breathing by 48 hours postnatal
|
|
• dramatic loss of motor neurons were observed in spinal cord (~35% loss) and facial nucleus(~40% loss) at postnatal day 5
• normal numbers of motor neurons were observed in spinal cord and facial nucleus in animals at postnatal day 1
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Werdnig-Hoffmann disease | DOID:13137 |
OMIM:253300 |
J:60592 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice survive over a year in contrast to mutants without Tg(SMN2*A111G)588Ahmb which exhibit embryonic lethality
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice survive over a year (some up to 1.5 years) compared to mutants not carrying the Tg(SMN2*A111G)591Ahmb transgene which have a median survival of 4.4-5 days
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice survive over a year (some up to 1.5 years) compared to mutants not carrying the Tg(SMN2*A111G)588Ahmb transgene which show a survival of 4.4-5 days
• animals have no obvious phenotype and are comparable to controls having normal mouse Smn
|
|
• muscle morphology changes suggest muscles have undergone denervation followed by re-innervation
|
|
• at 10 months, muscle fibers display hypertrophy with patches of atrophic fibers; average fiber size (mean size of 2870 um2) is greater than Tg(SMN2*A111G)588Ahmb/ Tg(SMN2*A111G)588Ahmb, Smn1tm1Msd/ + (carrier) controls (mean size of 2456 um2) and fiber distribution is shifted to larger range of 2800-3900 um2
|
| N |
• spinal cord have normal ventral root numbers relative to carrier controls
|
|
• at 10 months, muscle fibers display hypertrophy with patches of atrophic fibers; average fiber size (mean size of 2870 um2) is greater than Tg(SMN2*A111G)588Ahmb/ Tg(SMN2*A111G)588Ahmb, Smn1tm1Msd/ + (carrier) controls (mean size of 2456 um2) and fiber distribution is shifted to larger range of 2800-3900 um2
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice survive over a year (some up to 1.5 years) compared to mutants not carrying the Tg(SMN2*A111G)591Ahmb transgene which have a median survival of 4.4-5 days
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• animals have a mean lifespan of 6.5 days compared to spinal muscular atrophic (SMA) animals which do not carry the Tg(SMN2*)1951Ahmb transgene (4.4 day survival); Tg(SMN2*)1951Ahmb homozygosity does not significantly enhance survival
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• fewer than the expected numbers of mutants are seen at birth
|
|
• reduction in width of the interventricular septum at E17.5
|
|
• hearts have a thin and branched left ventricular wall at E17.5
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• thinner arterial wall
|
|
• the interventricular septum is partially flattened at P5 and P9
• the interventricular septum lacks the normal curvature which results in a D-shaped left ventricle
|
|
• reduction in width of the interventricular septum at P5 and P9, but not at P2
|
|
• enlargement of the left ventricle at P5 and P9
|
|
• interstitial fibrosis due to oxidative stress is initiated at P2 and progresses rapidly
|
|
• electrocardiogram indicates longer R-R intervals
|
|
• interstitial fibrosis due to oxidative stress is initiated at P2 and progresses rapidly
|
|
• marker analysis indicates oxidative stress in the heart
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Werdnig-Hoffmann disease | DOID:13137 |
OMIM:253300 |
J:164444 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• double mutants survive an average of 160 days, with some living up to a year
|
|
• muscle fiber distribution is different from normal muscle; mice have a greater number of smaller diameter fibers relative to controls
|
|
• tail becomes necrotic by 21 days of age, resulting in tail being very short
|
|
• tail becomes necrotic by 21 days of age, resulting in tail being very short
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• double mutants survive an average of 6.6 days, with some living past 15 days, representing a slight but significant increase compared to Smn1tm1Msd homozygotes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice exhibit motor neuron loss
|
|
• at 1 year of age, mice have significantly reduced root counts compared to mice homozygous for Smn1tm1Msd, Tg(Prnp-SMN)92Ahmb, and Tg(SMN2)89Ahmb
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Werdnig-Hoffmann disease | DOID:13137 |
OMIM:253300 |
J:131663 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice survive an average of 3.5 days, not significantly different from mean lifespan of 4.6 days of Smn1tm1Msd homozygotes
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Werdnig-Hoffmann disease | DOID:13137 |
OMIM:253300 |
J:131663 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• double mutants survive an average of 210 days, with many living more than 1 year
• lifespan is less than that of Smn1tm1Msd heterozygotes
|
|
• muscle fiber distribution is different from normal muscle; mice have a greater number of smaller diameter fibers relative to controls
|
| N |
• mice have normal motor neuron counts and lumbar root counts, compared to triple homozygotes for Smn1tm1Msd, Tg(ACTA1-SMN)63Ahmb, and Tg(SMN2)89Ahmb
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Werdnig-Hoffmann disease | DOID:13137 |
OMIM:253300 |
J:131663 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• axon sprouting occurs in gastrocnemius and triceps muscles
• sprouts are both nodal and emerge from the neuromuscular junction (terminal)
• otherwise, phenotype is indistinguishable from littermates
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mean survival is 227 days
|
|
• 29% fewer lumbar spinal cord neurons than control in 3.5 month old mice
• 19% fewer facial nucleus neurons than control
• 5 day old mice did not exhibit reduced numbers of motor neurons
|
|
• ventral roots from L1-L5 lumbar spinal cord region contain few myelinated axons
• remaining axons are shriveled and exhibit Wallerian degeneration
|
|
• increased number of neuromuscular junctions in gastrocnemius
|
|
• intranuclear aggregates (gems) of the SMN protein in spinal cord are fewer and less intense than in normal littermates
|
|
• reduced amplitudes in evoked muscle potentials from tibial nerve
|
|
• axon sprouting occurs in gastrocnemius and triceps muscles
• sprouts are both nodal and emerge from the neuromuscular junction (terminal)
|
|
• angulated and atrophic fibers observed in gastrocnemius and to a lesser extent in quadriceps and intercostal muscles
|
|
• samples from multiple pelvic and thoracic muscles exhibit abnormal spontaneous activity of single muscle fibers and of motor units in 4-6 month old mice
• abnormal activity is occasionally accompanied by biphasic sharp waves
|
|
• 20-40% smaller than normal littermates
|
|
• toward the end of life
|
|
• mice fail to groom efficiently toward the end of life
|
|
• muscle weakness exhibited by 3 weeks of age
|
|
• mice are less active by 3 weeks of age compared to normal littermates
• exhibit very little activity toward the end of life
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| juvenile spinal muscular atrophy | DOID:12376 |
OMIM:253400 |
J:81238 | |
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 04/23/2024 MGI 6.23 |
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