Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos

Abstract

Proximal spinal muscular atrophy is an autosomal recessive human disease of spinal motor neurons leading to muscular weakness with onset predominantly in infancy and childhood. With an estimated heterozygote frequency of 1͞40 it is the most common monogenic disorder lethal to infants; milder forms represent the second most common pediatric neuromuscular disorder. Two candidate genes-survival motor neuron (SMN) and neuronal apoptosis inhibitory protein have been identified on chromosome 5q13 by positional cloning. However, the functional impact of these genes and the mechanism leading to a degeneration of motor neurons remain to be defined. To analyze the role of the SMN gene product in vivo we generated SMN-deficient mice. In contrast to the human genome, which contains two copies, the mouse genome contains only one SMN gene. Mice with homozygous SMN disruption display massive cell death during early embryonic development, indicating that the SMN gene product is necessary for cellular survival and function.

Gemin3Is an Essential Gene Required for Larval Motor Function and Pupation inDrosophila

“…Complete loss of Smn function results in early embryonic lethality in mice (Schrank et al, 1997); animals that carry low-copy SMN2 transgenes survive embryogenesis but die postnatally, yet those with high-copy transgenes are completely viable (Hsieh-Li et al, 2000;Monani et al, 2000). Thus, SMA can be viewed as a "protein-dosage" disease, an interpretation that correlates well with the fact that SMA severity is inversely proportional to SMN protein levels (Coovert et al, 1997;Lefebvre et al, 1997).…”

“…To date, several Smn and Gemin2 alleles have been characterized. Null mutations in mouse Smn and Gemin2 are also early embryonic lethals (Schrank et al, 1997;Jablonka et al, 2002). Expression of a low-copy human SMN2 transgene rescues the embryonic lethality, but the mice die shortly after birth and display severe motor neuron degeneration and muscular atrophy phenotypes (Monani et al, 2000).…”

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

“…In 1995, the genetic basis of SMA was shown to be due to mutations or deletions of the Survival Motor Neuron 1 ( SMN1 ) gene 2. The encoded protein, termed SMN, is ubiquitous and complete knock out is embryonic lethal 3. Consistent with this, SMA is not a disease of complete absence of the SMN protein but rather due to the low basal levels of SMN produced by a second nearly identical copy of SMN1 , termed the SMN2 gene 4…”

SMN - A chaperone for nuclear RNP social occasions?

“…18 SMA is a common neuromuscular disorder, recognized as the most prevalent genetic cause of early childhood mortality. 19 Clinically, SMA patients show progressive muscle weakness of proximal muscle groups, ultimately leading to paralysis; death is typically caused by progressive and restrictive respiratory failure.…”