title: A leaky splicing mutation affecting SMN1 exon 7 inclusion explains an unexpected mild case of spinal muscular atrophy.
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.
authors.affiliation: Inserm U614, IFRMP, Institute for Biomedical Research, Rouen University Medical School, Rouen, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Vezain
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Gérard
authors.forename: Séverine
authors.initials: S
authors.lastname: Drunat
authors.forename: Benoît
authors.initials: B
authors.lastname: Funalot
authors.forename: Séverine
authors.initials: S
authors.lastname: Fehrenbach
authors.forename: Virginie
authors.initials: V
authors.lastname: N'Guyen-Viet
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vallat
authors.forename: Thierry
authors.initials: T
authors.lastname: Frébourg
authors.forename: Mario
authors.initials: M
authors.lastname: Tosi
authors.forename: Alexandra
authors.initials: A
authors.lastname: Martins
authors.forename: Pascale
authors.initials: P
authors.lastname: Saugier-Veber
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D001483:Base Sequence; D005091:Exons / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009134:Muscular Atrophy, Spinal / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*
chemical_list: D055533:Survival of Motor Neuron 1 Protein