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It has long been considered that cryptic splice sites are ignored by the splic-ing machinery in the context of intact genuine splice sites. In the present study, it is shown that cryptic splice sites are utilized in all circumstances, when the authentic site is intact, partially functional or completely abol-ished. | ễFEBS Journal Cryptic splicing sites are differentially utilized in vivo Amel Haj Khelil1 2 Mireille Deguillien1 Madeleine Moriniere1 Jemni Ben Chibani2 and Faouzi Baklouti1 1 CNRS UMR 5534 Centre de Genetique Moleculaire et Cellulaire Universite Lyon 1 Villeurbanne France 2 Laboratoire de Biochimie et Biologie Moleculaire Faculte de Pharmacie Monastir Tunisia Keywords cryptic splice site exon intron mRNA splicing mutation Correspondence F. Baklouti Centre de Genetique Moleculaire et Cellulaire - CNRS UMR 5534 Bat. Gregor Mendel Universite Lyon 1 16 rue RaphaelDubois 69622 Villeurbanne Cedex France Fax 33 4 72 43 26 85 Tel 33 4 72 43 29 28 E-mail faouzi.baklouti@univ-lyon1.fr Received 10 October 2007 revised 6 December 2007 accepted 8 January 2008 doi 10.1111 j.1742-4658.2008.06276.x It has long been considered that cryptic splice sites are ignored by the splicing machinery in the context of intact genuine splice sites. In the present study it is shown that cryptic splice sites are utilized in all circumstances when the authentic site is intact partially functional or completely abolished. Their use would therefore contribute to a background lack of fidelity in the context of the wild-type sequence. We also found that a mutation at the 5 splice site of b-globin intron 1 accomodates multiple cryptic splicing pathways including three previously reported pathways. Focusing on the two major cryptic 5 splice sites within b-globin exon 1 we show that cryptic splice site selection ex vivo varies depending upon a the cell stage of development during terminal erythroid differentiation b the nature of the mutation at the authentic 5 splice site and c the nature of the promoter. Finally we found that the two major cryptic 5 splice sites are utilized with differential efficiencies in two siblings sharing the same b-globin chromosome haplotype in the homozygous state. Collectively these data suggest that intrinsic sequence specific factors and cell genetic background factors .
