Htra2-β1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2)

Yvonne Hofmann, Christian L. Lorson, Stefan Stamm, Elliot Androphy, Brunhilde Wirth

Research output: Contribution to journalArticle

260 Citations (Scopus)

Abstract

Spinal muscular atrophy (SMA), a common motor neuron disease in humans, results from loss of functional survival motor neuron (SMN1) alleles. A nearly identical copy of the gene, SMN2, fails to provide protection from SMA because of a single translationally silent nucleotide difference in exon 7. This likely disrupts an exonic splicing enhancer and causes exon 7 skipping, leading to abundant production of a shorter isoform, SMN2Δ7. The truncated transcript encodes a less stable protein with reduced self-oligomerization activity that fails to compensate for the loss of SMN1. This report describes the identification of an in vivo regulator of SMN mRNA processing. Htra2-β1, an SR-like splicing factor and ortholog of Drosophila melanogaster transformer-2, promoted the inclusion of SMN exon 7, which would stimulate full-length SMN2 expression. Htra2-β1 specifically functioned through and bound an AG-rich exonic splicing enhancer in SMN exon 7. This effect is not species-specific as expression of Htra2-β1 in human or mouse cells carrying an SMN2 minigene dramatically increased production of full-length SMN2. This demonstrates that SMN2 mRNA processing can be modulated in vivo. Because all SMA patients retain at least one SMN2 copy, these results show that an in vivo modulation of SMN RNA processing could serve as a therapeutic strategy to prevent SMA.

Original languageEnglish (US)
Pages (from-to)9618-9623
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number17
StatePublished - Aug 15 2000
Externally publishedYes

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Motor Neurons
Spinal Muscular Atrophy
Exons
Motor Neuron Disease
Messenger RNA
Drosophila melanogaster
Cell Survival
Protein Isoforms
Nucleotides
Alleles
RNA
Genes
Proteins

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Htra2-β1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2). / Hofmann, Yvonne; Lorson, Christian L.; Stamm, Stefan; Androphy, Elliot; Wirth, Brunhilde.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 17, 15.08.2000, p. 9618-9623.

Research output: Contribution to journalArticle

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