AUTHOR=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. 

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

JOURNAL=Frontiers in Endocrinology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1166076

DOI=10.3389/fendo.2023.1166076

ISSN=1664-2392

ABSTRACT=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. Following the identification of a loss-of-function variant (p.Arg703Gln) in the PAM gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated pituitary adenomas kindreds for PAM variants. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides.
Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. No germline CNVs or somatic single nucleotide variants (SNVs) were identified. We detected seven, likely pathogenic, heterozygous missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with GH excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or with 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, for splicing by minigene assays, and for 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 PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction.
Identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.