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

Area of Science:

• Endocrinology and Genetics
• Molecular Biology

Background:

• Pituitary adenomas (PAs) are common tumors of the anterior pituitary gland, often without a known genetic cause, leading to hormonal dysregulation and clinical complications.
• The proprotein convertase 1/3 (PCSK1), also known as PAM, gene encodes a multifunctional enzyme crucial for peptide amidation, a key post-translational modification.

Approach:

• Investigated 299 individuals with sporadic PAs and 17 familial isolated pituitary adenoma kindreds for PAM gene variants using germline and tumor sequencing, alongside copy number variation (CNV) analysis.
• Performed in vitro functional assays, including Western blotting, minigene splicing assays, and analysis of amidation activity in cell lysates and serum, to assess the impact of identified variants.
• Analyzed 200,000 exomes from the UK Biobank to confirm the association between rare PAM single nucleotide variants (SNVs) and pituitary hyperfunction diagnoses.

Key Points:

• Identified seven likely pathogenic heterozygous missense, truncating, and regulatory SNVs in the PAM gene in patients with various types of PAs, including GH excess and pediatric Cushing disease.
• Functional testing confirmed that these PAM SNVs have a deleterious effect on protein expression, trafficking, splicing, and/or amidation activity.
• A significant association was found between the PAM gene, rare PAM SNVs, and diagnoses related to pituitary gland hyperfunction.

Conclusions:

• The PAM gene is implicated as a candidate gene associated with pituitary adenomas and hypersecretion.
• These findings open avenues for developing novel therapeutic strategies targeting PAM function for pituitary disorders.