Alternative splicing generates isoform diversity in MEN1.

Area of Science:

• Genetics and Molecular Biology
• Cancer Research
• Bioinformatics

Background:

• The tumor suppressor gene MEN1 has a dual role in cancer, acting as both a tumor suppressor and oncogene.
• The precise mechanisms underlying MEN1's complex functions are not fully understood.
• The well-characterized MENIN protein isoform 2 is encoded by MEN1.

Purpose of the Study:

• To investigate the hypothesis that diverse MENIN protein isoforms contribute to the complexity of MEN1 gene biology.
• To identify and characterize novel alternative splicing events in MEN1.
• To analyze the impact of genomic variants on different MENIN isoforms.

Main Methods:

• In silico data mining of splice junction data.
• Analysis of genomic variant databases (somatic and germline).
• Literature collation of MENIN function studies.

Main Results:

• Alternative splicing occurs throughout the MEN1 gene, generating diverse MENIN isoforms.
• MENIN isoform 2 is the most abundant transcript across tissues.
• Novel splicing events, including a new exon in intron 7, were identified, potentially altering protein interactions.
• 2574 unique MEN1 genomic variants were compiled, with several predicted to affect specific MENIN isoforms.
• The impact of MEN1 variants on 74 biological variables was summarized.

Conclusions:

• MEN1 biology is more complex than previously appreciated, with alternative splicing generating a diverse array of MENIN isoforms.
• MENIN isoform 2 is likely the primary reference isoform.
• Identified novel splicing events and variants provide a basis for further investigation into MENIN's functional diversity and role in cancer.
• Four specific MEN1 variants (MENIN^L22R, MENIN^H139D, MENIN^A242V, MENIN^W436R) are proposed for concurrent investigation to elucidate MENIN function.