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

[en] 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.</sec><sec>MethodsFollowing 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.</sec><sec>ResultsIn 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 PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction.</sec><sec>ConclusionThe identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

Disciplines :

Endocrinology, metabolism & nutrition

Author, co-author :

Trivellin, Giampaolo

Daly, Adrian ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'endocrinologie clinique

Hernández-Ramírez, Laura C.

Araldi, Elisa

Tatsi, Christina

Dale, Ryan K.

Fridell, Gus

Mittal, Arjun

Faucz, Fabio R.

Iben, James R.

More authors (20 more)

Language :

English

Title :

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

Publication date :

14 June 2023

Journal title :

Frontiers in Endocrinology

eISSN :

1664-2392

Publisher :

Frontiers Media S.A., Ch

Volume :

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://www.frontiersin.org/articles/10.3389/fendo.2023.1166076

Available on ORBi :

since 14 June 2023

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