Widespread production of novel soluble protein isoforms by alternative splicing removal of transmembrane anchoring domains.

We have investigated the effects of alternative splicing on transcripts encoding membrane proteins in 1001 human genes. Out of a total of 464 alternatively spliced genes encoding single-pass transmembrane (TM) proteins, in 188 we observed a splice form that specifically removed the TM domain, producing a soluble protein isoform. For example, in syndecan-4, the new alternative splice form closely parallels the proteolytic ectodomain shedding previously shown in this protein, and recognized as an important regulatory mechanism of receptor function. While many of the soluble isoforms produced by alternative splicing have already been validated, most are novel, and in 57 genes showed a statistically significant association (P-value<0.01) with a specific tissue.