The human RNF220 coding gene is located at Chr1: p34.1 (NCBI Gene ID: 55182). To date, four isoforms of the RNF220 protein have been described. Prior functional studies have investigated 70 kDa proteins, primarily isoform 1 but potentially isoform 3. Here, we show that the shorter isoforms of RNF220 that lack much of the N-terminus, the 353 AA isoform 2 and 308 AA isoform 4, are broadly expressed at high levels. While targets of RNF220 ubiquitination have been identified and their physiological roles elucidated [3,11], these studies have been limited to substrates of isoform 1. We hypothesized that the ubiquitous, highly expressed short isoforms may play a more fundamental role in most tissues. The shorter isoforms were found to perform distinct functions including in myoblast differentiation. These findings strongly argue for the investigation of these short isoforms in future studies on RNF220 function.