Table 1.
Mouse models of SMA
| Genotype | Severity of phenotypea | Notes | References |
|---|---|---|---|
| Smn−/− | ++++ | Death of embryo occurs prior to uterine implantation. | (Schrank et al., 1997) |
| Smn+/− | + | Early acute loss of lumbar spinal cord motor neurons (∼28% within 5 weeks), with subsequent slowly progressive reduction over an extended time scale. | (Jablonka et al., 2000; Balabanian et al., 2007) |
| Smn−/−; SMN2(2Hung)+/+ | + to +++ | Transgene including human SMN2, SERF1 and part of NAIP; rescues embryonic lethality of Smn−/−. Transgene copy number correlates with disease severity, which ranges from death within 1 week to normal survival. |
(Hsieh-Li et al., 2000) |
| Smn−/−; SMN2(89Ahmb)+/+ | + to +++ | Transgene containing only the SMN2 locus, rescues Smn−/− embryonic lethality. 42/56 mice with one or two transgene copies were stillborn or died before 6 hours, with the remainder dying between 4–6 days. Mice with eight copies of the transgene reach adulthood. |
(Monani et al., 2000) |
| SmnF7/Δ7; NSE-Cre+ | ++ |
SmnF7/Δ7 mice with Cre-loxP-mediated deletion of Smn exon 7 in neuronal tissue. Mean lifespan: 25 days. |
(Frugier et al., 2000; Cifuentes-Diaz et al., 2002) |
| SmnF7/Δ7; HSA-Cre+ | ++ |
SmnF7/Δ7 mice with Cre-loxP-mediated deletion of Smn exon 7 in myoblasts and post-mitotic fused myotubes of skeletal muscle. Mean lifespan: 33 days. |
(Cifuentes-Diaz et al., 2001) |
| Smn+/−; Gemin2+/− | + | Mice with heterozygous deletion of Smn and Gemin2 display an accelerated loss of motor neurons compared with Smn+/− mice. | (Jablonka et al., 2002) |
| Smn−/−; SMN2(89Ahmb)+/−; SMN1(A2G)+/− | + | Mean survival of mice with a single A2G transgene and one copy of SMN2 is 227 days, whereas mice homozygous for A2G are relatively indistinguishable from controls. | (Monani et al., 2003) |
| SmnF7/F7; HSA-Cre+ | + |
SmnF7/F7 mice with Cre-loxP-mediated deletion of Smn exon 7 in post-mitotic fused myotubes of skeletal muscle. Without heterozygous deletion of Smn exon 7 in all somatic cells, animals live for a median of 8 months. |
(Nicole et al., 2003) |
| SmnF7/F7; NSE-Cre+ | ++ |
SmnF7/F7mice with Cre-loxP-mediated deletion of Smn exon 7 in neuronal tissue. Mean lifespan: 31±2 days. |
(Ferri et al., 2004) |
| SmnF7/F7; Alfp-Cre+ | ++++ |
SmnF7/F7 mice with Cre-loxP-mediated deletion of Smn exon 7 in hepatocytes. Causes late embryonic lethality at E18. Heterozygous deletion has no obvious effect. |
(Vitte et al., 2004) |
| Smn−/−; SMN2(89Ahmb)+/+; SMNΔ7+/+ | +++ | Transgene containing human SMNΔ7, the predominant isoform produced by SMN2; improves the phenotype of Smn−/−; SMN2+/+. Mean lifespan: 13.3±0.3 days. |
(Le et al., 2005) |
| Smn−/−; SMN2+/+; SMN1(A111G)+/− | + | Transgene containing the SMN1 allele seen in Type I and II patients; improves survival to over 1 year with no obvious phenotype. | (Workman et al., 2009) |
| Smn−/−; SMN2+/+; SMN1(VDQNQKE)+/− | +++ | Transgene containing SMN1 exons 1–6 with an additional motif; has little effect on lifespan extension. | (Workman et al., 2009) |
| Smn2B/− | ++ |
Smn transgene harboring three nucleotide substitutions within the exonic splicing enhancer of exon 7. Mean lifespan: 28 days. |
(Bowerman et al., 2009) |
| Smn−/−; SMN2(N11)+/−; SMN2(N46)+/− | +++ | Mice with three copies of SMN2 were generated by crossing strains with two (N11) and four (N46) copies. Mean lifespan: 15.2±0.4 days. |
(Michaud et al., 2010) |
| SmnF7/−; SMN2(89Ahmb)+/+; Olig2-Cre+ | + |
SmnF7/−; SMN2+/+ mice (i.e. Smn+/−; SMN2+/+) with Cre-loxP-mediated deletion of Smn exon 7 in spinal cord motor neuron progenitor cells. ∼70% of mutants survived to 12 months, yet were clearly distinguishable from controls. |
(Park et al., 2010) |
| Smn1tm1Cdid/tm1Cdid; CreEsr1 and Smn1tm2Cdid/tm2Cdid; CreEsr1 | ++++ | Inducible Smn alleles that mimic SMN2 splicing are homozygous embryonic lethal (E12.5–E15.5) and normal when heterozygous. In the presence of Cre recombinase, loxP-flanked neomycin (Neo) gene resistance cassettes situated in Smn intron 7 are excised, producing full-length Smn. When crossed with a tamoxifen-inducible Cre allele (CreEsr1), early embryonic induction of full-length Smn by tamoxifen can rescue embryonic lethality. |
(Hammond et al., 2010) |
a
+, mild; ++, moderate; +++, severe; ++++, embryonic lethal.
SmnF7/Δ7 mice are Smn+/Δ7, and SmnF7/F7 mice are Smn+/+.