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

被引:266
作者
Hofmann, Y
Lorson, CL
Stamm, S
Androphy, EJ
Wirth, B [1 ]
机构
[1] Univ Bonn, Inst Human Genet, D-53111 Bonn, Germany
[2] Tufts Univ, Sch Med, Boston, MA 02111 USA
[3] Tufts Univ New England Med Ctr, Dept Dermatol, Boston, MA 02111 USA
[4] Max Planck Inst Neurobiol, D-82152 Martinsried, Germany
关键词
D O I
10.1073/pnas.160181697
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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, SMN2 Delta 7. The truncated transcript encodes a less stable protein with reduced self-oligomerization activity that fails to compensate for the toss of SMN1. This report describes the identification of an in vivo regulator of SMN mRNA processing. Htra2-beta 1, 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-beta 1 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-beta 1: 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.
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页码:9618 / 9623
页数:6
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