Seemingly Neutral Polymorphic Variants May Confer Immunity to Splicing-Inactivating Mutations: A Synonymous SNP in Exon 5 of MCAD
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- 作者：Karsten Bork Nielsen ; Suzette Sø ; rensen ; Luca Cartegni ; Thomas Juhl Corydon ; Thomas Koed Doktor ; Lisbeth Dahl Schroeder ; Line Sinnathamby Reinert ; Orly Elpeleg ; Adrian R. Krainer ; Niels Gregersen ; Jø ; rgen Kjems ; Brage Storstein Andresen
- 刊名：The American Journal of Human Genetics
- 出版年：2007
- 出版时间：March 2007
- 年：2007
- 卷：80
- 期：3
- 页码：416-432
- 全文大小：1438 K
文摘
The idea that point mutations in exons may affect splicing is intriguing and adds an additional layer of complexity when evaluating their possible effects. Even in the best-studied examples, the molecular mechanisms are not fully understood. Here, we use patient cells, model minigenes, and in vitro assays to show that a missense mutation in exon 5 of the medium-chain acyl-CoA dehydrogenase (MCAD) gene primarily causes exon skipping by inactivating a crucial exonic splicing enhancer (ESE), thus leading to loss of a functional protein and to MCAD deficiency. This ESE functions by antagonizing a juxtaposed exonic splicing silencer (ESS) and is necessary to define a suboptimal 3′ splice site. Remarkably, a synonymous polymorphic variation in MCAD exon 5 inactivates the ESS, and, although this has no effect on splicing by itself, it makes splicing immune to deleterious mutations in the ESE. Furthermore, the region of MCAD exon 5 that harbors these elements is nearly identical to the exon 7 region of the survival of motor neuron (SMN) genes that contains the deleterious silent mutation in SMN2, indicating a very similar and finely tuned interplay between regulatory elements in these two genes. Our findings illustrate a mechanism for dramatic context-dependent effects of single-nucleotide polymorphisms on gene-expression regulation and show that it is essential that potential deleterious effects of mutations on splicing be evaluated in the context of the relevant haplotype.