title: 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.
authors.affiliation: Molecular Neurogenetics Laboratory, INSERM E-223, 2 rue Gaston Crémieux, CP5724, 91057 Evry, France.
authors.forename: Jérémie M
authors.initials: JM
authors.lastname: Vitte
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Davoult
authors.forename: Natacha
authors.initials: N
authors.lastname: Roblot
authors.forename: Michèle
authors.initials: M
authors.lastname: Mayer
authors.forename: Vandana
authors.initials: V
authors.lastname: Joshi
authors.forename: Sabrina
authors.initials: S
authors.lastname: Courageot
authors.forename: François
authors.initials: F
authors.lastname: Tronche
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Vadrot
authors.forename: Marie Helene
authors.initials: MH
authors.lastname: Moreau
authors.forename: François
authors.initials: F
authors.lastname: Kemeny
authors.forename: Judith
authors.initials: J
authors.lastname: Melki
mesh_terms: D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein; D005091:Exons; D017353:Gene Deletion; D005799:Genes, Dominant; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D019426:Integrases / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D013997:Time Factors; D019076:Transgenes
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D007501:Iron; C045073:Cre recombinase; D019426:Integrases