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A leaky splicing mutation affecting SMN1 exon 7 inclusion explains an unexpected mild case of spinal muscular atrophy
Author(s) -
Vezain Myriam,
Gérard Bénédicte,
Drunat Séverine,
Funalot Benoît,
Fehrenbach Séverine,
N'GuyenViet Virginie,
Vallat JeanMichel,
Frébourg Thierry,
Tosi Mario,
Martins Alexandra,
SaugierVeber Pascale
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21528
Subject(s) - smn1 , exon , spinal muscular atrophy , biology , sma* , rna splicing , mutation , intron , genetics , splice site mutation , alternative splicing , minigene , microbiology and biotechnology , gene , rna , mathematics , combinatorics
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. Hum Mutat 32:989–994, 2011. © 2011 Wiley‐Liss, Inc.