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Genomic variants in exons and introns: identifying the splicing spoilers

Nature Reviews Genetics volume 5, pages 389–396 (2004)Cite this article

Abstract

When genome variants are identified in genomic DNA, especially during routine analysis of disease-associated genes, their functional implications might not be immediately evident. Distinguishing between a genomic variant that changes the phenotype and one that does not is a difficult task. An increasing amount of evidence indicates that genomic variants in both coding and non-coding sequences can have unexpected deleterious effects on the splicing of the gene transcript. So how can benign polymorphisms be distinguished from disease-associated splicing mutations?

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Figure 1: Splicing reactions and essential splicing signals.
Figure 2: Regulatory elements in pre-mRNA splicing and GVs that can affect them.

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Acknowledgements

This work was supported by the Telethon Onlus Foundation, Italy, the Fondo Investimenti per la Ricerca di Base and the Associazione Italiana per la Ricerca sul Cancro.

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Authors and Affiliations

  1. International Centre for Genetic Engineering and Biotechnology, Padriciano 99, Trieste, 34012, Italy

    Franco Pagani & Francisco E. Baralle

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  1. Franco Pagani
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  2. Francisco E. Baralle
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Correspondence to Francisco E. Baralle.

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Related links

Related links

DATABASES

LocusLink

ATM

BRCA1

CFTR

NF1

Scn8a

SMN1

SMN2

OMIM

cystic fibrosis

spinal muscular atrophy

Swiss-Prot

hnRNPA1

FURTHER INFORMATION

Cystics Fibrosis Mutation Database

Glossary

ALTERNATIVELY SPLICED ISOFORMS

RNA isoforms that are generated by alternative use of splice sites, which leads to variation in which exons are included in the mRNA and subsequently translated.

ATAXIA TELANGIECTASIA

An autosomal recessive disorder that involves cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition.

COMPOSITE EXONIC REGULATORY ELEMENT OF SPLICING

(CERES). Short exonic RNA sequences (5–12 bases) that contain overlapping enhancer and silencer sequences. The presence of such elements is indicated when scanning mutagenesis analyses reveal that different mutations at nearby positions or even at the same position have opposite effects on splicing efficiency.

CRYPTIC SPLICE SITES

Pseudo splice sites that are activated as a consequence of a mutation elsewhere in the gene.

EXON SKIPPING

Exclusion of an exon that is normally included in the mRNA.

EXON SPLICING ENHANCER AND EXON SPLICING SILENCER (ESE, ESS); INTRON SPLICING ENHANCER AND INTRON SPLICING SILENCER (ISE, ISS)

Sequences in the pre-mRNA that enhance or reduce the efficiency of splicing. In general, exonic enhancers or silencers are shorter (∼6 bases) than the intronic ones, which can be hundreds of bases long.

HETEROGENOUS NUCLEAR RIBONUCLEOPROTEIN PARTICLES

(hnRNP). A class of diverse RNA-binding proteins that associate with nascent pre-mRNA.

HYBRID MINIGENE

A simplified laboratory version of a natural gene that contains one of more of the gene's exons and introns.

NEUROFIBROMATOSIS TYPE 1

An autosomal dominant disorder that is particularly characterized by cafe-au-lait spots and fibromatous tumours of the skin.

PSEUDO EXON

A pre-mRNA sequence that resembles an exon, both in its size and the presence of flanking pseudo splice sites, but that the splicing machinery does not normally recognize.

PSEUDO SPLICE SITES

Sequences that are identical to normal splice sites but that are not normally used in splicing.

SIMPLE SEQUENCE REPEAT

A sequence that consists largely of a tandem repeat of a specific K-mer (such as (TG)11).

SITE-DIRECTED MUTAGENESIS

A method that is used to substitute a specific nucleotide into a DNA sequence.

TRANSESTERIFICATION

A reaction that breaks and makes chemical bonds (in this case, phosphodiester bonds) in a coordinated transfer so that energy is required.

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Pagani, F., Baralle, F. Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 5, 389–396 (2004). https://doi.org/10.1038/nrg1327

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