The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: Causes and consequences

来自掌桥科研

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184

作者：

M Krawczak，J Reiss，DN Cooper

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摘要：

Summary. A total of 101 different examples of point mu- tations, which lie in the vicinity of mRNA splice junc- tions, and which have been held to be responsible for a human genetic disease by altering the accuracy of effi- ciency of mRNA splicing, have been collated. These data comprise 62 mutations at 5' splice sites, 26 at 3' splice sites and 13 that result in the creation of novel splice sites. It is estimated that up to 15% of all point mutations causing human genetic disease result in an mRNA splicing defect. Of the 5' splice site mutations, 60% involved the invariant GT dinucleotide; mutations were found to be non-randomly distributed with an ex- cess over expectation at positions + 1 and +2, and appar- ent deficiencies at positions - 1 and -2. Of the 3' splice site mutations, 87% involved the invariant AG dinuc- leotide; an excess of mutations over expectation was noted at position -2. This non-randomness of mutation reflects the evolutionary conservation apparent in splice site consensus sequences drawn up previously from pri- mate genes, and is most probably attributable to detec- tion bias resulting from the differing phenotypic severity of specific lesions. The spectrum of point mutations was also drastically skewed: purines were significantly over- represented as substituting nucleotides, perhaps because of steric hindrance (e.g. in U1 snRNA binding at 5' splice sites). Furthermore, splice sites affected by point mutations resulting in human genetic disease were mark- edly different from the splice site consensus sequences. When similarity was quantified by a 'consensus value', both extremely low and extremely high values were nota- bly absent from the wild-type sequences of the mutated splice sites. Splice sites of intermediate similarity to the consensus sequence may thus be more prone to the de- leterious effects of mutation. Regarding the phenotypic effects of mutations on mRNA splicing, exon skipping occurred more frequently than cryptic splice site usage. Evidence is presented that indicates that, at least for 5' splice site mutations, cryptic splice site usage is favoured

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关键词：

Humans Genetic Diseases, Inborn RNA Precursors RNA, Messenger RNA Splicing Consensus Sequence Phenotype Point Mutation Genes Introns