期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 9, 页码 3426-3431出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0700343104
关键词
alternative splicing; exonic splicing silencer; hnRNP All; intronic splicing silencer
The neurodegenerative disease spinal muscular atrophy is caused by mutation of the survival motor neuron 1 (SMN1) gene. SMN2 is a nearly identical copy of SMN1 that is unable to prevent disease, because most SMN2 transcripts lack exon 7 and thus produce a nonfunctional protein. A key cause of inefficient SMN2 exon 7 splicing is a single nucleotide difference between SMN1 and SMN2 within exon 7. We previously provided evidence that this base change suppresses exon 7 splicing by creating an inhibitory element, a heterogeneous nuclear ribonucleoprotein (hnRNP) Aldependent exonic splicing silencer. We now find that another rare nucleoticle difference between SMN1 and SMN2, in intron 7, potentially creates a second SMN2-specific hnRNP Al binding site. Remarkably, this single base change does indeed create a highaffinity hnRNP All binding site, and base substitutions that disrupt it restore exon 7 inclusion in vivo and prevent hnRNP A1 binding in vitro. We propose that interactions between hnRNP A1 molecules bound to the exonic and intronic sites cooperate to exclude exon 7 and discuss the significance of this exclusion with respect to SMN expression and splicing control more generally.
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