Alternative splicing generates isoform diversity in MEN1

Abstract

Although the gene MEN1 has a long association with cancer, its mechanisms of action remain incompletely understood, being both a tumour suppressor in neuroendocrine tumours and 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 datamining, we show alternative splicing along the entire length of MEN1. Splice junction data suggests 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 in 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 summarise the impact of MEN1 variants on 74 biological variables. We propose a set of 4 MEN1 variants, MENINL22R, MENINH139D, MENINA242V and MENINW436R, that represent a cohort with different biological properties, that should be investigated concurrently to better dissect MENIN function.