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A leaky splicing mutation affecting SMN1 exon 7 inclusion explains an unexpected mild case of spinal muscular atrophy

Myriam Vezain 1 Bénédicte Gérard 2 Séverine Drunat 3 Benoît Funalot 4 Séverine Fehrenbach Virginie N'Guyen-Viet Jean-Michel Vallat 5 Thierry Frebourg 6, 1 Mario Tosi 6, 1 Alexandra Martins 7, 1, 8 Pascale Saugier-Veber 9, 1
1 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
2 Service d'hématologie et immunologie
3 AP-HP Hôpital universitaire Robert-Debré [Paris]
4 Service de Génétique Médicale [CHU Necker]
5 Service de Neurologie [CHU Limoges]
6 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
7 GMFC - Génétique du cancer et des maladies neuropsychiatriques
8 Inserm U614, IFRMP, Institute for Biomedical Research, Rouen University Medical School, Rouen, France
9 Service de génétique [Rouen]
Abstract : Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder resulting, in most cases, from homozygous deletions of the SMN1 gene or, in rare cases, from SMN1 intragenic mutations. Here we describe the identification and characterization of c.835-3C>T, a novel SMA-causing mutation detected in the intron 6 of the single SMN1 allele of a type IV SMA patient. We demonstrate both ex vivo and in vivo that c.835-3C>T is a deleterious splicing mutation that induces a modest but unequivocal exclusion of exon 7 from the SMN1 transcripts, its "leakiness" explaining the exceptionally mild phenotype of this patient. This mutation creates a putative high-affinity binding site for the splicing repressor protein hnRNP A1 overlapping the splice acceptor site of exon 7 (UAG|GGU). Our findings support the current therapeutic strategies aiming at correcting exon 7 splicing in SMA patients, and bring clues about the level of exon 7 inclusion required to achieve a therapeutic effect.
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02336367
Contributor : Alexandra Martins <>
Submitted on : Monday, October 28, 2019 - 5:44:31 PM
Last modification on : Friday, June 11, 2021 - 8:38:03 AM

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COMUE-NORMANDIE | UNIROUEN | UNIV-PARIS7 | USPC | GPMCND | UNIV-PARIS

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Myriam Vezain, Bénédicte Gérard, Séverine Drunat, Benoît Funalot, Séverine Fehrenbach, et al.. A leaky splicing mutation affecting SMN1 exon 7 inclusion explains an unexpected mild case of spinal muscular atrophy. Human Mutation, Wiley, 2011, 32 (9), pp.989-994. ⟨10.1002/humu.21528⟩. ⟨hal-02336367⟩

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