Alternative (mis)splicing and disease

Proper splicing regulation is important for an organism. Point mutations in splice sites cause an estimated 15% of genetic defects in humans. Due to the growing awareness of the importance of alternative splicing, this number has constantly increased in the last years. We are investigating the alternative splicing patterns of two genes, tau and SMN2 (survival of motoneuron 2) in more detail, because point mutations in exonic enhancers in these genes result in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and spinal muscular atrophy, respectively. We could show that in both systems changes in phosphorylation influence splice site selection, which could be the basis of a novel therapeutic approach. We found that tau exon 10 and its regulatory factor tra2-beta1 is altered in Alzheimer?s disease. This suggests that human diseases associated with missplicing could be the result of a ?wrong? combination of regulatory factors. In an European consortium that I coordinate, we have therefore developed an ?alternative exon chip? together with the necessary bioinformatic tools. This allows us now to elucidate the cellular code regulating splice site selection.

An important finding of the human genome project is the abundance of small non-coding RNAs. We were the first to demonstrate that such small RNAs (snoRNAs) regulate alternative pre-mRNA splicing. The lack of expression of one of this snoRNAs causes Prader-Willi-syndrome by misregulating an alternative splicing pattern of a serotonin receptor. This represents a complete novel mechanism of alternative splice site selection leading to a human disease.