THE ASSOCIATION OF NONSENSE CODONS WITH EXON SKIPPING

Authors
Citation
Cr. Valentine, THE ASSOCIATION OF NONSENSE CODONS WITH EXON SKIPPING, Mutation research. Reviews in mutation research, 411(2), 1998, pp. 87-117
Citations number
133
Language
INGLESE
art.tipo
Review
Categorie Soggetti
Genetics & Heredity",Toxicology,"Biothechnology & Applied Migrobiology
ISSN journal
1383-5742
Volume
411
Issue
2
Year of publication
1998
Pages
87 - 117
Database
ISI
SICI code
1383-5742(1998)411:2<87:TAONCW>2.0.ZU;2-V
Abstract
Some genes that contain premature nonsense codons express alternativel y-spliced mRNA that has skipped the exon containing the nonsense codon . This paradoxical association of translation signals (nonsense codons ) and RNA splicing has inspired numerous explanations. The first is ba sed on the fact that premature nonsense codons often reduce mRNA abund ance, The reduction in abundance of full-length mRNA then allows more efficient amplification during PCR of normal, minor, exon-deleted prod ucts. This mechanism has been demonstrated to explain an extensive cor relation between nonsense codons and exon-skipping for the hamster Hpr t gene. The second explanation is that the mutation producing an in-fr ame nonsense codon has an effect on exon definition. This has been dem onstrated for the Mup and hamster Hprt gene by virtue of the fact that missense mutations at the same sites also are associated with the sam e exon-deleted mRNA, The third general explanation is that a hypotheti cal process takes place in the nucleus that recognizes nonsense codons , termed 'nuclear scanning', which then has an effect on mRNA splicing , Definitive evidence for nuclear scanning is lacking. My analysis of both nonsense and missense mutations associated with exon skipping in a large number of genes revealed that both types of mutations frequent ly introduce a T into a purine-rich DNA sequence and are often within 30 base pairs of the nearest exon boundary. This is intriguing given t hat purine-rich splicing enhancers are known to be inhibited by the in troduction of a T. Almost all mutations associated with exon skipping occur in purine-rich or A/C-rich sequences, also characteristics of sp licing enhancers. I conclude that most cases of exon skipping associat ed with premature termination codons may be adequately explained eithe r by a structural effect on exon definition or by nonquantitative meth ods to measure mRNA, rather than an effect on a putative nuclear scann ing mechanism. (C) 1998 Elsevier Science B.V. All rights reserved.