Titre :
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A genetic approach to the critical molecular pathway in spinal muscular atrophy using zebrafish and mice
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contenu dans :
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Auteurs :
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Congrès international de myologie 2008 (International Congress of Myology 2008; 26-30 mai 2008; Marseille, France) ;
Burghes A ;
Workman E ;
McGovern V ;
Saieva L ;
Pellizzoni L ;
Beattie C
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Type de document :
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Article
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Année de publication :
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2008
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Pages :
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p. 44
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Langues:
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Anglais
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Mots-clés :
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amyotrophie spinale
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axone
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colloque
;
gène SMN1
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gène SMN2
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jonction neuromusculaire
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mécanisme d'action
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modèle génétique
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mutation génétique
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poisson zèbre
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protéine SMN
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snRNP
;
souris amyotrophie spinale
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Résumé :
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Spinal muscular atrophy is caused by loss or mutation of the SMN1 gene and retention of SMN2, leading to low levels of functional SMN. A major function of SMN is assembly of the heptameric Sm ring onto snRNA with SMA tissues having reduced activity which in particular affects the snRNPs critical for splicing of the minor introns. Reduction of SMN levels in zebrafish results in motor axon and NMJ defects. Severe SMN missense mutations apart from SMNA111G lack the ability to perform snRNP assembly whereas mild mutations have reduced assembly activity. SMA mice show normal motor axon outgrowth and patterning but do show abnormalities at the NMJ. We have investigated missense alleles of SMN with various properties for the ability to rescue both zebrafish and SMA mice. From this analysis we conclude that rescue of SMA is directly correlated with the ability of an allele to perform snRNP assembly. In particular high level expression of SMNA111G allele can rescue lethality of one copy SMN2 mice and they do not present with SMA. However low level expression does not rescue either lethality or SMA. Interestingly, high expression of the SMNA111G allele cannot rescue embryonic lethality of Smn-/- mice which have no SMN2. This indicates that homomeric complexes of SMNA111G are not functional whereas heteromeric complexes are functional. We suggest that these heteromeric complexes consist of a wild type SMN subunit allowing the loading of a single snRNA. Further analysis will use allelic complementation to ask whether the same or different functions are disrupted by SMN missense mutations so as to define critical partners of SMN in SMA. In addition we are currently developing a genetic model of SMA in zebrafish that can be used to perform unbiased suppressor screens and thus define the critical pathways downstream of SMN assembly activity.
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