Mouse Genome Informatics
cn1
    Olig2tm1(cre)Tmj/Olig2+
Smn1tm1Jme/Smn1tm1Msd
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb

involves: 129 * 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• about 70% of mutants survive to about 12 months of age
• about 30% of mutants die before 12 months of age

growth/size/body
• by the second day after birth, mutants show a 15% decrease in weight compared to controls

behavior/neurological
• mutants exhibit reduced grip strength, indicating weakness

muscle
• 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

nervous system
• 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

skeleton

Mouse Models of Human Disease
OMIM IDRef(s)
Spinal Muscular Atrophy, Type I; SMA1 253300 J:164292


Mouse Genome Informatics
cn2
    Olig2tm1(cre)Tmj/Olig2+
Smn1tm1Jme/Smn1tm1Msd
Tg(SMN2)89Ahmb/0

involves: 129 * 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging


Mouse Genome Informatics
cn3
    Mnx1tm4(cre)Tmj/Mnx1+
Smn1tm1Cdid/Smn1tm1Cdid
Tg(SMN2)89Ahmb/0

involves: 129 * 129S1/Sv * C57BL/6 * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• median survival of 12 days

nervous system
N
• neuromuscular junctions are similar to controls in the intercostal and triangularis sterni muscles (J:183080)
• decrease in cardiac autonomic innervation
• in L3-L5 spinal cord sections but not in the cervical or thoracic regions

cardiovascular system
• end-stage mice display skipped or dropped beats
• at P9-P11
• at P9-P11

behavior/neurological
N
• ambulatory throughout life (J:183080)
• lateral instability of the hind limbs
• significantly improved righting response
• early in life
• outgrow this passive behavior after P6

growth/size/body

Mouse Models of Human Disease
OMIM IDRef(s)
Spinal Muscular Atrophy, Type I; SMA1 253300 J:183080


Mouse Genome Informatics
cx4
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb

B6.Cg-Tg(SMN2)89Ahmb Smn1tm1Msd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice do not survive past 8 days with a mean survival of 5 days

growth/size/body


Mouse Genome Informatics
cx5
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/0

B6.Cg-Tg(SMN2)89Ahmb Smn1tm1Msd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice do not survive past 2 days with a mean survival of 1 day


Mouse Genome Informatics
cx6
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/0
Tg(SMN2*delta7)4299Ahmb/0

FVB.Cg-Tg(SMN2)89Ahmb Smn1tm1Msd Tg(SMN2*delta7)4299Ahmb
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice do not survive past 16 days with a mean survival of 10 days


Mouse Genome Informatics
cx7
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb
Tg(SMN2*delta7)4299Ahmb/Tg(SMN2*delta7)4299Ahmb

FVB.Cg-Tg(SMN2)89Ahmb Smn1tm1Msd Tg(SMN2*delta7)4299Ahmb
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice do not survive past 17 days with a mean survival of 13 days

behavior/neurological
• 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

nervous system
• 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

muscle
• at P14, muscle fibers of the gastrocnemius are small due to atrophy

growth/size/body

Mouse Models of Human Disease
OMIM IDRef(s)
Spinal Muscular Atrophy, Type I; SMA1 253300 J:97103


Mouse Genome Informatics
cx8
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb
Tg(SMN2*delta7)4299Ahmb/Tg(SMN2*delta7)4299Ahmb

FVB.Cg-Tg(SMN2)89Ahmb Smn1tm1Msd Tg(SMN2*delta7)4299Ahmb/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• average survival of about 2 weeks

nervous system
• 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
• muscle fiber diameter is decreased in both slow- and fast-twitch muscles compared to in wild-type mice

cardiovascular system
• 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

growth/size/body
• begin to lose weight at around P10

Mouse Models of Human Disease
OMIM IDRef(s)
Spinal Muscular Atrophy, Type I; SMA1 253300 J:164446


Mouse Genome Informatics
cx9
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb
Tg(SMN2*delta7)4299Ahmb/0

FVB.Cg-Tg(SMN2)89Ahmb Smn1tm1Msd Tg(SMN2*delta7)4299Ahmb/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mean lifespan is 13 days

growth/size/body

cardiovascular system
• mutants exhibit an increase in cardiac fibrosis compared to unaffected wild-type controls

muscle


Mouse Genome Informatics
cx10
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb

FVB.Cg-Tg(SMN2)89Ahmb Smn1tm1Msd/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• 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
• muscle fiber diameter is decreased in both slow- and fast-twitch muscles compared to in wild-type mice

growth/size/body

mortality/aging
• mean lifespan is 7 days


Mouse Genome Informatics
cx11
    Smn1tm1Cdid/Smn1tm1Cdid
Tg(SMN2)89Ahmb/0

involves: 129 * C57BL/6 * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• median survival is 7 days

nervous system
• 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

cardiovascular system
• by P3 and declines over time

behavior/neurological
• never develop the ability to right when placed on the back
• near complete paralysis by P5

growth/size/body
• at P2 or later

Mouse Models of Human Disease
OMIM IDRef(s)
Spinal Muscular Atrophy, Type I; SMA1 253300 J:183080


Mouse Genome Informatics
cx12
    Smn1tm1Cdid/Smn1tm1.1Cdid
Tg(SMN2)89Ahmb/0

involves: 129 * C57BL/6 * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
normal phenotype
• viable and indistinguishable from control littermates


Mouse Genome Informatics
cx13
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN1-SMN2*)16Cll/0
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb

involves: 129P2/OlaHsd * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 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

growth/size/body
• 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

behavior/neurological
N
• mutants are more agile and generally fitter than double homozygous Smn1tm1Msd and Tg(SMN2)89Ahmb control mice (J:194969)
• 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)

muscle
• 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

nervous system
• 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

cardiovascular system
• 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

integument
• mutants start to show signs of necrosis on the ears, tails, and/or eyes at approximately P40-P50

Mouse Models of Human Disease
OMIM IDRef(s)
Spinal Muscular Atrophy, Type I; SMA1 253300 J:194969


Mouse Genome Informatics
cx14
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/?

involves: 129P2/OlaHsd * C57BL/6J * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 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

behavior/neurological
• 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

muscle
N
• no musculature atrophy was detected in the quadriceps or gastrocnemius of mice that survived 4-6 days (J:60592)

respiratory system
• mice that survived 4-6 days displayed labored breathing by 48 hours postnatal

nervous system
• 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
OMIM IDRef(s)
Spinal Muscular Atrophy, Type I; SMA1 253300 J:60592


Mouse Genome Informatics
cx15
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN1*A2G)2023Ahmb/0
Tg(SMN2)89Ahmb/0

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mean survival is 227 days

nervous system
• 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)

muscle
• 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

growth/size/body
• 20-40% smaller than normal littermates
• toward the end of life

reproductive system

behavior/neurological
• mice fail to groom efficiently toward the end of life
• muscle weakness exhibited by 3 weeks of age
• exhibit very little activity toward the end of life
• mice are less active by 3 weeks of age compared to normal littermates

respiratory system
• mice exhibit short, shallow breeding toward the end of life

Mouse Models of Human Disease
OMIM IDRef(s)
Spinal Muscular Atrophy, Type III; SMA3 253400 J:81238


Mouse Genome Informatics
cx16
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN1*A2G)2023Ahmb/Tg(SMN1*A2G)2023Ahmb
Tg(SMN2)89Ahmb/?

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• 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


Mouse Genome Informatics
cx17
    Smn1tm1Msd/Smn1tm1Msd
Tg(Prnp-SMN)92Ahmb/Tg(Prnp-SMN)92Ahmb
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• double mutants survive an average of 210 days, with many living more than 1 year
• lifespan is less than that of Smn1tm1Msd heterozygotes

muscle
• muscle fiber distribution is different from normal muscle; mice have a greater number of smaller diameter fibers relative to controls

nervous system
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 (J:131663)

Mouse Models of Human Disease
OMIM IDRef(s)
Spinal Muscular Atrophy, Type I; SMA1 253300 J:131663


Mouse Genome Informatics
cx18
    Smn1tm1Msd/Smn1tm1Msd
Tg(Prnp-SMN)92Ahmb/0
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• double mutants survive an average of 150 days


Mouse Genome Informatics
cx19
    Smn1tm1Msd/Smn1tm1Msd
Tg(ACTA1-SMN)69Ahmb/Tg(ACTA1-SMN)69Ahmb
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 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
OMIM IDRef(s)
Spinal Muscular Atrophy, Type I; SMA1 253300 J:131663


Mouse Genome Informatics
cx20
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN1*A2G)2023Ahmb/0
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• 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
OMIM IDRef(s)
Spinal Muscular Atrophy, Type I; SMA1 253300 J:131663


Mouse Genome Informatics
cx21
    Smn1tm1Msd/Smn1tm1Msd
Tg(ACTA1-SMN)63Ahmb/0
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 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


Mouse Genome Informatics
cx22
    Smn1tm1Msd/Smn1tm1Msd
Tg(ACTA1-SMN)63Ahmb/Tg(ACTA1-SMN)63Ahmb
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• double mutants survive an average of 160 days, with some living up to a year

muscle
• muscle fiber distribution is different from normal muscle; mice have a greater number of smaller diameter fibers relative to controls

limbs/digits/tail
• tail becomes necrotic by 21 days of age, resulting in tail being very short


Mouse Genome Informatics
cx23
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/0
Tg(SMN2*A111G)588Ahmb/0

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• mice survive over a year in contrast to mutants without Tg(SMN2*A111G)588Ahmb which exhibit embryonic lethality (J:148541)


Mouse Genome Informatics
cx24
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/0
Tg(SMN2*A111G)591Ahmb/0

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
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 (J:148541)


Mouse Genome Informatics
cx25
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb
Tg(SMN2*A111G)588Ahmb/0

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
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 (J:148541)
• animals have no obvious phenotype and are comparable to controls having normal mouse Smn (J:148541)

muscle
• 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

nervous system
N
• spinal cord have normal ventral root numbers relative to carrier controls (J:148541)


Mouse Genome Informatics
cx26
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb
Tg(SMN2*A111G)591Ahmb/0

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
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 (J:148541)


Mouse Genome Informatics
cx27
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb
Tg(SMN2*)1951Ahmb/0

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 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


Mouse Genome Informatics
cx28
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• fewer than the expected numbers of mutants are seen at birth

cardiovascular system
• reduction in width of the interventricular septum at E17.5
• hearts have a thin and branched left ventricular wall at E17.5


Mouse Genome Informatics
cx29
    Smn1tm1Msd/Smn1tm1Msd
Tg(SMN2)89Ahmb/Tg(SMN2)89Ahmb
Tg(SMN2*delta7)4299Ahmb/Tg(SMN2*delta7)4299Ahmb

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• 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

cellular
• marker analysis indicates oxidative stress in the heart

Mouse Models of Human Disease
OMIM IDRef(s)
Spinal Muscular Atrophy, Type I; SMA1 253300 J:164444