Frontiers in Endocrinology (Jun 2023)
Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion
- Giampaolo Trivellin,
- Giampaolo Trivellin,
- Adrian F. Daly,
- Laura C. Hernández-Ramírez,
- Laura C. Hernández-Ramírez,
- Elisa Araldi,
- Christina Tatsi,
- Ryan K. Dale,
- Gus Fridell,
- Arjun Mittal,
- Fabio R. Faucz,
- Fabio R. Faucz,
- James R. Iben,
- Tianwei Li,
- Eleonora Vitali,
- Stanko S. Stojilkovic,
- Peter Kamenicky,
- Chiara Villa,
- Chiara Villa,
- Bertrand Baussart,
- Bertrand Baussart,
- Prashant Chittiboina,
- Camilo Toro,
- William A. Gahl,
- Erica A. Eugster,
- Luciana A. Naves,
- Marie-Lise Jaffrain-Rea,
- Marie-Lise Jaffrain-Rea,
- Wouter W. de Herder,
- Sebastian JCMM Neggers,
- Patrick Petrossians,
- Albert Beckers,
- Andrea G. Lania,
- Andrea G. Lania,
- Richard E. Mains,
- Betty A. Eipper,
- Constantine A. Stratakis,
- Constantine A. Stratakis,
- Constantine A. Stratakis
Affiliations
- Giampaolo Trivellin
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Giampaolo Trivellin
- IRCCS Humanitas Research Hospital, Milan, Italy
- Adrian F. Daly
- Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium
- Laura C. Hernández-Ramírez
- Red de Apoyo a la Investigación, Coordinación de la Investigación Científica, Universidad Nacional Autónoma de México e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Laura C. Hernández-Ramírez
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
- Elisa Araldi
- Energy Metabolism Laboratory, Department of Health Sciences and Technology, Institute of Translational Medicine, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland
- Christina Tatsi
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
- Ryan K. Dale
- Bioinformatics and Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
- Gus Fridell
- Bioinformatics and Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
- Arjun Mittal
- Bioinformatics and Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
- Fabio R. Faucz
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
- Fabio R. Faucz
- Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
- James R. Iben
- Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
- Tianwei Li
- Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
- Eleonora Vitali
- IRCCS Humanitas Research Hospital, Milan, Italy
- Stanko S. Stojilkovic
- Section on Cellular Signaling, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
- Peter Kamenicky
- 0Université Paris-Saclay, Institut national de la santé et de la recherche médicale (INSERM), Physiologie et Physiopathologie Endocriniennes, Le Kremlin-Bicêtre, France
- Chiara Villa
- 1Département de Neuropathologie de la Pitié Salpêtrière, Hôpital de la Pitié-Salpêtrière - Assistance Publique–Hôpitaux de Paris (APHP) Sorbonne Université, Paris, France
- Chiara Villa
- 2Institut national de la santé et de la recherche médicale (INSERM) U1016, Centre national de la recherche scientifique Unité Mixte de Recherche (CNRS UMR) 8104, Institut Cochin, Paris, France
- Bertrand Baussart
- 2Institut national de la santé et de la recherche médicale (INSERM) U1016, Centre national de la recherche scientifique Unité Mixte de Recherche (CNRS UMR) 8104, Institut Cochin, Paris, France
- Bertrand Baussart
- 3Service de Neurochirurgie, Hôpital Pitié-Salpêtrière, AP-HP Sorbonne, Paris, France
- Prashant Chittiboina
- 4Neurosurgery Unit for Pituitary and Inheritable Diseases and Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, United States
- Camilo Toro
- 5National Institutes of Health (NIH) Undiagnosed Diseases Program, Office of the Clinical Director, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD, United States
- William A. Gahl
- 5National Institutes of Health (NIH) Undiagnosed Diseases Program, Office of the Clinical Director, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD, United States
- Erica A. Eugster
- 6Division of Endocrinology and Diabetes, Department of Pediatrics, Riley Hospital for Children at Indiana University (IU) Health, Indiana University School of Medicine, Indianapolis, IN, United States
- Luciana A. Naves
- 7Service of Endocrinology, University Hospital, Faculty of Medicine, University of Brasilia, Brasilia, Brazil
- Marie-Lise Jaffrain-Rea
- 8Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
- Marie-Lise Jaffrain-Rea
- 9Neuromed Institute, Istituto di Ricovero e Cura a Carattere Scientifico, Pozzilli, Italy
- Wouter W. de Herder
- 0Department of Medicine, Section Endocrinology, Pituitary Center Rotterdam, Erasmus University Medical Center, Rotterdam, Netherlands
- Sebastian JCMM Neggers
- 0Department of Medicine, Section Endocrinology, Pituitary Center Rotterdam, Erasmus University Medical Center, Rotterdam, Netherlands
- Patrick Petrossians
- Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium
- Albert Beckers
- Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium
- Andrea G. Lania
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Andrea G. Lania
- IRCCS Humanitas Research Hospital, Milan, Italy
- Richard E. Mains
- 1Department of Neuroscience, University of Connecticut (UConn) Health, Farmington, CT, United States
- Betty A. Eipper
- 2Department of Molecular Biology and Biophysics, UConn Health, Farmington, CT, United States
- Constantine A. Stratakis
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
- Constantine A. Stratakis
- 3Human Genetics and Precision Medicine, Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology Hellas, Heraklion, Greece
- Constantine A. Stratakis
- 4Research Institute, ELPEN, Athens, Greece
- DOI
- https://doi.org/10.3389/fendo.2023.1166076
- Journal volume & issue
-
Vol. 14
Abstract
IntroductionPituitary 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.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.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.ConclusionThe identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.
Keywords
- peptidylglycine α-amidating monooxygenase
- amidation
- gigantism
- acromegaly
- Cushing disease
- pituitary tumors
