Abstract：
:Spinal muscular atrophy is a neurodegenerative disorder caused by the deletion or mutation of the survival-of-motor-neuron gene, SMN1. An SMN1 paralog, SMN2, differs by a C-->T transition in exon 7 that causes substantial skipping of this exon, such that SMN2 expresses only low levels of functional protein. A better understanding of SMN splicing mechanisms should facilitate the development of drugs that increase survival motor neuron (SMN) protein levels by improving SMN2 exon 7 inclusion. In addition, exonic mutations that cause defective splicing give rise to many genetic diseases, and the SMN1/2 system is a useful paradigm for understanding exon-identity determinants and alternative-splicing mechanisms. Skipping of SMN2 exon 7 was previously attributed either to the loss of an SF2/ASF-dependent exonic splicing enhancer or to the creation of an hnRNP A/B-dependent exonic splicing silencer, as a result of the C-->T transition. We report the extensive testing of the enhancer-loss and silencer-gain models by mutagenesis, RNA interference, overexpression, RNA splicing, and RNA-protein interaction experiments. Our results support the enhancer-loss model but also demonstrate that hnRNP A/B proteins antagonize SF2/ASF-dependent ESE activity and promote exon 7 skipping by a mechanism that is independent of the C-->T transition and is, therefore, common to both SMN1 and SMN2. Our findings explain the basis of defective SMN2 splicing, illustrate the fine balance between positive and negative determinants of exon identity and alternative splicing, and underscore the importance of antagonistic splicing factors and exonic elements in a disease context.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Cartegni L,Hastings ML,Calarco JA,de Stanchina E,Krainer ARdoi
10.1086/498853subject
Has Abstractpub_date
2006-01-01 00:00:00pages
63-77issue
1eissn
0002-9297issn
1537-6605pii
S0002-9297(07)60806-4journal_volume
78pub_type
杂志文章abstract：:Hereditary gingival fibromatosis (HGF) is a rare, autosomal dominant form of gingival overgrowth. Affected individuals have a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of the oral masticatory mucosa. Genetic loci for autosomal dominant forms of HGF have been localized to chromosome 2p21-p22 (HGF1...
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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更新日期：1978-05-01 00:00:00
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journal_title：American journal of human genetics
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更新日期：1996-06-01 00:00:00
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journal_title：American journal of human genetics
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更新日期：1989-04-01 00:00:00
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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