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hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing.
Hum Mol Genet. 2007 Dec 15; 16(24):3149-59.HM

Abstract

Homozygous deletion or mutation of the survival of motor neuron 1 gene (SMN1) causes spinal muscular atrophy. SMN1 has been duplicated in humans to create SMN2, which produces a low level of functional SMN protein. However, most SMN2 transcripts lack exon 7, resulting in a non-functional protein. A single nucleotide difference near the 5' end of exon 7 largely accounts for SMN2 exon 7 skipping, an effect that has been attributed to loss of an exonic splicing enhancer (ESE) dependent on the SR protein splicing factor ASF/SF2 or to the creation of an exonic splicing silencer (ESS) element that functions by binding of the splicing repressor hnRNP A1. Our earlier experiments favored the latter mechanism and here we provide further evidence supporting the ESS model. We demonstrate that the striking effect of hnRNP A1 depletion on SMN2 exon 7 splicing is specific, as hnRNP A1 depletion has little or no effect on other inefficient splicing events tested, and ASF/SF2 depletion does not affect SMN1/2 splicing. By two different methods, we find a strong and specific interaction of hnRNPA1 with SMN2 exon 7 and only weak and equivalent interactions between ASF/SF2 and other SR proteins with the 5' ends of SMN1 and SMN2 exon 7. Finally, we describe two disease-related exon-skipping mutations that create hnRNP A1 binding sites, but show that splicing can be restored only modestly or not at all by hnRNP A1 depletion. Together our results provide strong support for the idea that SMN2 exon 7 splicing is repressed by an hnRNPA1-dependent ESS, but also indicate that creation of such elements is context-dependent.

Authors+Show Affiliations

Department of Biological Sciences, Columbia University, New York, NY 10027, USA. kashima_t@jikei.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17884807

Citation

Kashima, Tsuyoshi, et al. "HnRNP A1 Functions With Specificity in Repression of SMN2 Exon 7 Splicing." Human Molecular Genetics, vol. 16, no. 24, 2007, pp. 3149-59.
Kashima T, Rao N, David CJ, et al. HnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing. Hum Mol Genet. 2007;16(24):3149-59.
Kashima, T., Rao, N., David, C. J., & Manley, J. L. (2007). HnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing. Human Molecular Genetics, 16(24), 3149-59.
Kashima T, et al. HnRNP A1 Functions With Specificity in Repression of SMN2 Exon 7 Splicing. Hum Mol Genet. 2007 Dec 15;16(24):3149-59. PubMed PMID: 17884807.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing. AU - Kashima,Tsuyoshi, AU - Rao,Nishta, AU - David,Charles J, AU - Manley,James L, Y1 - 2007/09/19/ PY - 2007/9/22/pubmed PY - 2008/3/15/medline PY - 2007/9/22/entrez SP - 3149 EP - 59 JF - Human molecular genetics JO - Hum Mol Genet VL - 16 IS - 24 N2 - Homozygous deletion or mutation of the survival of motor neuron 1 gene (SMN1) causes spinal muscular atrophy. SMN1 has been duplicated in humans to create SMN2, which produces a low level of functional SMN protein. However, most SMN2 transcripts lack exon 7, resulting in a non-functional protein. A single nucleotide difference near the 5' end of exon 7 largely accounts for SMN2 exon 7 skipping, an effect that has been attributed to loss of an exonic splicing enhancer (ESE) dependent on the SR protein splicing factor ASF/SF2 or to the creation of an exonic splicing silencer (ESS) element that functions by binding of the splicing repressor hnRNP A1. Our earlier experiments favored the latter mechanism and here we provide further evidence supporting the ESS model. We demonstrate that the striking effect of hnRNP A1 depletion on SMN2 exon 7 splicing is specific, as hnRNP A1 depletion has little or no effect on other inefficient splicing events tested, and ASF/SF2 depletion does not affect SMN1/2 splicing. By two different methods, we find a strong and specific interaction of hnRNPA1 with SMN2 exon 7 and only weak and equivalent interactions between ASF/SF2 and other SR proteins with the 5' ends of SMN1 and SMN2 exon 7. Finally, we describe two disease-related exon-skipping mutations that create hnRNP A1 binding sites, but show that splicing can be restored only modestly or not at all by hnRNP A1 depletion. Together our results provide strong support for the idea that SMN2 exon 7 splicing is repressed by an hnRNPA1-dependent ESS, but also indicate that creation of such elements is context-dependent. SN - 0964-6906 UR - https://www.unboundmedicine.com/medline/citation/17884807/hnRNP_A1_functions_with_specificity_in_repression_of_SMN2_exon_7_splicing_ DB - PRIME DP - Unbound Medicine ER -