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

• Published in: Frontiers in endocrinology (Lausanne) Vol. 14; p. 1166076
• Main Authors: Trivellin, Giampaolo, Daly, Adrian F., Hernández-Ramírez, Laura C., Araldi, Elisa, Tatsi, Christina, Dale, Ryan K., Fridell, Gus, Mittal, Arjun, Faucz, Fabio R., Iben, James R., Li, Tianwei, Vitali, Eleonora, Stojilkovic, Stanko S., Kamenicky, Peter, Villa, Chiara, Baussart, Bertrand, Chittiboina, Prashant, Toro, Camilo, Gahl, William A., Eugster, Erica A., Naves, Luciana A., Jaffrain-Rea, Marie-Lise, de Herder, Wouter W., Neggers, Sebastian JCMM, Petrossians, Patrick, Beckers, Albert, Lania, Andrea G., Mains, Richard E., Eipper, Betty A., Stratakis, Constantine A.
• Format: Journal Article Web Resource
• Language: English
• Published: Switzerland Frontiers 14.06.2023; Frontiers Media S.A
• Subjects: acromegaly; amidation; Child; Cushing disease; DNA Copy Number Variations; Endocrinologie, métabolisme & nutrition; Endocrinology; Endocrinology, metabolism & nutrition; gigantism; Human health and pathology; Human health sciences; Humans; Life Sciences; Mixed Function Oxygenases; peptidylglycine α-amidating monooxygenase; Pituitary Diseases; Pituitary Gland; Pituitary Neoplasms - genetics; pituitary tumors; Sciences de la santé humaine; amidation; gigantism; peptidylglycine α-amidating monooxygenase; acromegaly; Cushing disease; pituitary tumors; peptidylglycine a-amidating monooxygenase amidation gigantism acromegaly Cushing disease pituitary tumors; peptidylglycine a-amidating monooxygenase
• ISSN: 1664-2392; 1664-2392
• DOI: 10.3389/fendo.2023.1166076

Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Following the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. In germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the gene and rare with diagnoses linked to pituitary gland hyperfunction. The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.