Multiple Endocrine Neoplasia Type 1 (MEN1) 5'UTR Deletion, in MEN1 Family, Decreases Menin Expression

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disorder caused by mutations in the MEN1 gene, typically affecting its coding region.
• Standard genetic testing for MEN1 often focuses on coding sequences, potentially missing pathogenic variants in regulatory regions.

Purpose of the Study:

• To investigate the genetic basis of MEN1 in a family with discordant tumor phenotypes despite identical twin status, where coding region analysis was negative.
• To identify novel mutations in the untranslated regions (UTRs) of the MEN1 gene that could explain disease pathogenesis.

Main Methods:

• Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) were used to analyze the MEN1 gene in affected and unaffected family members.
• Luciferase reporter assays were performed to assess the functional impact of a identified 5' UTR deletion on MEN1 promoter activity.
• Quantitative reverse transcription PCR (qRT-PCR) and Western blot analysis were employed to measure MEN1 mRNA and menin protein levels.

Main Results:

• A heterozygous 596bp deletion (Δ596bp) was identified in the 5' untranslated region (UTR) of the MEN1 gene, encompassing the core promoter and cis-regulatory elements.
• This deletion significantly reduced MEN1 promoter activity by 37-fold in HEK293 cells and 16-fold in BON-1 cells.
• The Δ596bp mutation led to substantial decreases in MEN1 mRNA (84%) and menin protein (88%) levels in affected individuals.

Conclusions:

• This study reports the first identified germline mutation in the 5' UTR of the MEN1 gene.
• The findings underscore the importance of analyzing UTRs in MEN1 patients with negative coding region mutation analyses.
• This 5' UTR deletion is a novel pathogenic mechanism contributing to MEN1 development by impairing gene expression.