Alternative splicing generates isoform diversity in MEN1.

Although the gene MEN1 has a long-standing association with cancer, its mechanisms of action remain incompletely understood, acting both as a tumour suppressor in neuroendocrine tumours and as an oncogene in leukaemia. The best-characterised isoform of the encoded protein, MENIN, is the 610-amino acid MENIN isoform 2. We hypothesise that some of the complexity of MEN1 biology can be attributed to a currently unappreciated contribution of different MENIN isoforms. Through in silico data mining, we show alternative splicing along the entire length of MEN1. Splice junction data suggest that the transcript encoding MENIN isoform 2 is the most abundant in all tissues examined, making a strong argument for this to be the reference transcript/protein isoform of MEN1. We also report novel splicing events, including a novel exon from within intron 7 that is relatively highly expressed in many tissues. These splicing events are predicted to contribute to MENIN diversity by generating isoforms with in-frame insertions, deletions or unique amino termini that, in turn, could have altered interactions with partner proteins. Finally, we have compiled 2574 unique genomic variants reported in MEN1 within somatic and germline databases and have identified several variants that could impact individual MENIN isoforms. We have also collated studies pertinent to MENIN function in the literature and summarised the impact of MEN1 variants on 74 biological variables. We propose a set of four MEN1 variants, MENIN^L22R, MENIN^H139D, MENIN^A242V and MENIN^W436R, that represent a cohort with different biological properties, which should be investigated concurrently to better dissect MENIN function.