Individuals with mutations in the ATM gene develop ataxia-telangiectasia, a neurodegenrative disorder characterized by immunological defects and cancer predisposition. In an Advanced Online Publication from Nature Genetics, Franco Pagani and colleagues describe a new kind of ATM mutation that leads to an unusual splicing defect (Nat Genet 2002, DOI:10.1038/ng858).

The mutant ATM allele contains a four-nucleotide deletion (GTAA) within intron 20. This deletion results in the inclusion of a 65 nucleotide 'cryptic exon' in the ATM mRNA. The ATM sequence, termed intron-splicing processing element (ISPE), is complementary to U1 snRNA. Experiments with a hybrid minigene confirmed the importance of the ISPE sequence; interaction with U1 snRNA affected the efficiency of intron removal. Introduction of the ISPE sequence into a different genomic context, exon 9 of the cystic fibrosis transmembrane regulator (CFTR) gene, caused exon skipping and splicing defects.

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