Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion

Area of Science:

• Endocrinology
• Human Genetics
• Molecular Biology

Background:

• Pituitary adenomas (PAs) are common tumors often lacking a known genetic cause, leading to hormonal dysregulation.
• The peptidylglycine a-amidating monooxygenase (PAM) protein is crucial for the C-terminal amidation of secreted peptides.

Purpose of the Study:

• To investigate the role of the PAM gene in the development of pituitary adenomas.
• To identify genetic variants in PAM associated with pituitary hyperfunction.

Main Methods:

• Screening of 299 individuals with sporadic PAs and 17 familial PA kindreds for PAM variants using germline and tumor sequencing.
• Germline copy number variation (CNV) analysis was performed.
• Functional in vitro testing of detected single nucleotide variants (SNVs) for effects on protein expression, trafficking, splicing, and amidation activity.

Main Results:

• Seven heterozygous, likely pathogenic PAM SNVs were identified in individuals with growth hormone excess, pediatric Cushing disease, and other PAs.
• In vitro functional assays confirmed deleterious effects of these SNVs on PAM protein expression and/or function.
• Analysis of UK Biobank exomes confirmed a significant association between the PAM gene, rare PAM SNVs, and pituitary hyperfunction.

Conclusions:

• The PAM gene is a novel candidate gene associated with pituitary hypersecretion.
• Targeting PAM function presents a potential therapeutic strategy for pituitary hyperfunction disorders.