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A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy
Open accessAbstract
SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical question is why only the homozygous loss of SMN1 , and not SMN2 , results in spinal muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybrid genes and a new SMN1 mutation showed a direct relationship between presence of disease and exon 7 skipping. We have reported previously that the exon-skipped product SMNΔ7 is partially defective for self-association and SMN self-oligomerization correlated with clinical severity. To evaluate systematically which of the five nucleotides that differ between SMN1 and SMN2 effect alternative splicing of exon 7, a series of SMN minigenes was engineered and transfected into cultured cells, and their transcripts were characterized. Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a translationally silent variance, was necessary and sufficient to dictate exon 7 alternative splicing. Thus, the failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer. These findings demonstrate the molecular genetic basis for the nature and pathogenesis of SMA and illustrate a novel disease mechanism. Because individuals with SMA retain the SMN2 allele, therapy targeted at preventing exon 7 skipping could modify clinical outcome.
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Metadata
- Authors
- Lorson, C. L., Hahnen, E., Androphy, E. J., & Wirth, B.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 1999-05-25
- Volume
- 96
- Issue
- 11
- Pages
- 6307-6311
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2054380003
- Cited by
- 1,532
- References
- 0
- FWCI
- 17.07
- Type
- journal article
- Language
- en
- Open access
- green
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