Deletion of Murine Smn Exon 7 Directed to Liver Leads to Severe Defect of Liver Development Associated with Iron Overload

Abstract

Spinal muscular atrophy (SMA) is characterized by degeneration of lower motor neurons caused by mutations of the survival motor neuron 1 gene (SMN1). SMN is involved in various processes including the formation of the spliceosome, pre-mRNA splicing and transcription. To know whether SMN has an essential role in all mammalian cell types or an as yet unknown specific function in the neuromuscular system, deletion of murine Smn exon 7, the most frequent mutation found among SMA patients, has been restricted to liver. Homozygous mutation results in severe impairment of liver development associated with iron overload and lack of regeneration leading to dramatic liver atrophy and late embryonic lethality of mutant mice. These data strongly suggest an ubiquitous and essential role of full-length SMN protein in various mammalian cell types. In SMA patients, the residual amount of SMN allows normal function of various organs except motor neurons. However, data from mouse and human suggest that other tissues might be involved in severe form of SMA or during prolonged disease course which reinforce the need of therapeutic approaches targeted to all tissues. In addition, liver function of patients should be carefully investigated and followed up before and during therapeutic trials.

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

“…However, splenic iron metabolism was not investigated in the latter study. Interestingly, impaired liver development, iron overload and embryonic lethality were the main features of Smn conditional knockout restricted to the liver 35. Recently, iron homeostasis defects were also observed in the Taiwanese mouse model of SMA 36.…”

Abnormal motor phenotype in the SMNΔ7 mouse model of spinal muscular atrophy

“…Loss of mSmn results in embryonic lethality in the mouse suggesting that the mSmn gene product is essential for cell function and survival (Schrank et al, 1997). Conditional knockdown of mSmn in various cell types including neurons, differentiated myocytes and hepatocytes also leads to death of those cells (CifuentesDiaz et al, 2002;Nicole et al, 2003;Vitte et al, 2004). Furthermore, reduction of SMN protein levels in zebrafish results in abnormalities in motor neuron-specific axon pathfinding (McWhorter et al, 2003).…”

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

“…Of therapeutic relevance, increasing the excitability of motor circuits through the pharmacological inhibition of K + channels ameliorated SMA in animal models [93]. Further evidence of the wider impact of SMN deficiency in disease pathogenesis comes from abnormalities in Schwann cells, skeletal muscle, heart, bone, pancreas, liver, hippocampus, thalamus, and the vascular system [94][95][96][97][98][99][100][101]. Controversy remains over the relative contribution of organ systems other than the motor neuron in SMN1-related SMA pathogenesis.…”