Positive and negative elements mediate control of alternative splicing in the AMPD1 gene

The second exon of the AMP deaminase (AMPD) 1 gene is alternatively spliced in response to stage-specific signals elaborated during myocyte differenti ation. Since inheritance of the mutation in exon 2 of the AMPD1 gene has be en recently shown to be associated with a better prognosis of congestive he art failure and the alternative splicing of exon 2 modulates the residual a ctivity of AMPD1 in individuals with this mutant allele, the regulatory mec hanism of alternative splicing in the AMPD1 gene is clinically intriguing. Retention or exclusion of exon 2 results from the interplay between negativ e and positive elements in the primary transcript. Exon 2 is intrinsically defective and difficult to recognize. Herein, we show that this property of exon 2 is the consequence of three defects; a suboptimal 3' splice accepto r site, a suboptimal 5' splice donor site and the small size of the exon. A n improvement in any one of these defects relieves the masking of this exon . Further, this defective exon can only be identified in the presence of th e adjacent downstream intron. (C) 2000 Elsevier Science B.V. All rights res erved.