Normal and abnormal mechanisms of gene splicing and relevance to inherited skin diseases

The process of excising introns from pre-mRNA complexes is directed by specific genomic DNA sequences at intron-exon borders known as splice sites. These regions contain well-conserved motifs which allow the splicing process to proceed in a regulated and structured manner. However, as well as conventional splicing, several genes have the inherent capacity to undergo alternative splicing, thus allowing synthesis of multiple gene transcripts, perhaps with different functional properties. Within the human genome, therefore, through alternative splicing, it is possible to generate over 100,000 physiological gene products from the 35,000 or so known genes. Abnormalities in normal or alternative splicing, however, account for about 15% of all inherited single gene disorders, including many with a skin phenotype. These splicing abnormalities may arise through inherited mutations in constitutive splice sites or other critical intronic or exonic regions. This review article examines the process of normal intron-exon splicing, as well as what is known about alternative splicing of human genes. The review then addresses pathological disruption of normal intron-exon splicing that leads to inherited skin diseases, either resulting from mutations in sequences that have a direct influence on splicing or that generate cryptic splice sites. Examples of aberrant splicing, especially for the COL7A1 gene in patients with dystrophic epidermolysis bullosa, are discussed and illustrated. The review also examines a number of recently introduced computational tools that can be used to predict whether genomic DNA sequences changes may affect splice site selection and how robust the influence of such mutations might be on splicing.