MUTYH-associated polyposis (MAP) is an autosomal recessive syndrome that predisposes to colorectal disease and cancer. In this issue, Plotz et al. (Hum Mutat 33:1067–1074, 2012) carefully analyze patterns of expression of the alternative transcript isoforms of MUTYH, coding for a protein involved in base excision repair. In studying lymphocytes of colorectal cancer patients and unaffected controls, and also within tissues of different origin, they describe a SNP that may elicit a detrimental effect on the cellular DNA repair processes by altering the ratio of particular MUTYH isoforms.
Different isoforms of proteins are generated through alternative splicing of pre-mRNA, as well as use of alternate transcriptional start and poly-adenylation sites. They can be tissue specific and/or localize to different sub-cellular compartments - for example, use of a different MUTYH first exon can produce a mitochondrial protein rather than a nuclear-localized one. Plotz et al. describe how one particular SNP can alter the MUTYH isoform ratio, depleting a colonic epithelial cell nuclear isoform. They propose it as a disease risk allele, particularly within the context of the recessive MAP syndrome.
With the gathering of genetic variation data in its many forms - for example, the 1000 Genomes Project and the Human Variome Project - and with some participants in these large consortia trying to address variation and disease phenotype, information on which gene isoforms are important in the diseased tissue of interest will be critical to help assess the variants involved in disease risk. The increasing knowledge of human variation and its association with disease risk through GWAS and re-sequencing projects requires expanded understanding of how these alterations affect tissue specific protein-coding transcripts or non-coding RNAs. Further understanding of which tissues/organs the variants affect most may allow targeted and appropriate clinical screening of carriers. Interesting times lie ahead!