Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion
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 multifunctio...
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| Published in | Frontiers in endocrinology (Lausanne) Vol. 14; p. 1166076 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article Web Resource |
| Language | English |
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14.06.2023
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| 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. 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. |
|---|---|
| AbstractList | 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.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.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.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.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 PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction.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.The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.ConclusionThe identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function. 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. 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. 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. 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. 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. |
| Author | Hernández-Ramírez, Laura C. Neggers, Sebastian JCMM Trivellin, Giampaolo Kamenicky, Peter Mittal, Arjun Toro, Camilo Jaffrain-Rea, Marie-Lise Stojilkovic, Stanko S. Beckers, Albert Petrossians, Patrick Li, Tianwei Vitali, Eleonora Chittiboina, Prashant Baussart, Bertrand Stratakis, Constantine A. Eipper, Betty A. Iben, James R. Villa, Chiara Gahl, William A. de Herder, Wouter W. Naves, Luciana A. Mains, Richard E. Eugster, Erica A. Fridell, Gus Lania, Andrea G. Tatsi, Christina Dale, Ryan K. Faucz, Fabio R. Daly, Adrian F. Araldi, Elisa |
| AuthorAffiliation | 20 Department of Medicine, Section Endocrinology, Pituitary Center Rotterdam, Erasmus University Medical Center , Rotterdam , Netherlands 1 Department of Biomedical Sciences, Humanitas University , Milan , Italy 17 Service of Endocrinology, University Hospital, Faculty of Medicine, University of Brasilia , Brasilia , Brazil 19 Neuromed Institute, Istituto di Ricovero e Cura a Carattere Scientifico , Pozzilli , Italy 16 Division 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 22 Department of Molecular Biology and Biophysics, UConn Health , Farmington, CT , United States 3 Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman , Liège , Belgium 21 Department of Neuroscience, University of Connecticut (UConn) Health , Farmington, CT , United States 2 IRCCS Humanitas Research Hosp |
| AuthorAffiliation_xml | – name: 9 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 – name: 17 Service of Endocrinology, University Hospital, Faculty of Medicine, University of Brasilia , Brasilia , Brazil – name: 14 Neurosurgery 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 – name: 23 Human Genetics and Precision Medicine, Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology Hellas , Heraklion , Greece – name: 1 Department of Biomedical Sciences, Humanitas University , Milan , Italy – name: 22 Department of Molecular Biology and Biophysics, UConn Health , Farmington, CT , United States – name: 24 Research Institute, ELPEN , Athens , Greece – name: 10 Université Paris-Saclay, Institut national de la santé et de la recherche médicale (INSERM), Physiologie et Physiopathologie Endocriniennes , Le Kremlin-Bicêtre , France – name: 18 Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila , L’Aquila , Italy – name: 3 Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman , Liège , Belgium – name: 16 Division 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 – name: 12 Institut 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 – name: 2 IRCCS Humanitas Research Hospital , Milan , Italy – name: 19 Neuromed Institute, Istituto di Ricovero e Cura a Carattere Scientifico , Pozzilli , Italy – name: 20 Department of Medicine, Section Endocrinology, Pituitary Center Rotterdam, Erasmus University Medical Center , Rotterdam , Netherlands – name: 15 National 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 – name: 7 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 – name: 21 Department of Neuroscience, University of Connecticut (UConn) Health , Farmington, CT , United States – name: 6 Energy Metabolism Laboratory, Department of Health Sciences and Technology, Institute of Translational Medicine, Swiss Federal Institute of Technology (ETH) Zurich , Schwerzenbach , Switzerland – name: 8 Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) , Bethesda, MD , United States – name: 4 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 – name: 11 Département de Neuropathologie de la Pitié Salpêtrière, Hôpital de la Pitié-Salpêtrière - Assistance Publique–Hôpitaux de Paris (APHP) Sorbonne Université , Paris , France – name: 5 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 – name: 13 Service de Neurochirurgie, Hôpital Pitié-Salpêtrière, AP-HP Sorbonne , Paris , France |
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| Copyright | Copyright © 2023 Trivellin, Daly, Hernández-Ramírez, Araldi, Tatsi, Dale, Fridell, Mittal, Faucz, Iben, Li, Vitali, Stojilkovic, Kamenicky, Villa, Baussart, Chittiboina, Toro, Gahl, Eugster, Naves, Jaffrain-Rea, de Herder, Neggers, Petrossians, Beckers, Lania, Mains, Eipper and Stratakis. Distributed under a Creative Commons Attribution 4.0 International License Copyright © 2023 Trivellin, Daly, Hernández-Ramírez, Araldi, Tatsi, Dale, Fridell, Mittal, Faucz, Iben, Li, Vitali, Stojilkovic, Kamenicky, Villa, Baussart, Chittiboina, Toro, Gahl, Eugster, Naves, Jaffrain-Rea, de Herder, Neggers, Petrossians, Beckers, Lania, Mains, Eipper and Stratakis 2023 Trivellin, Daly, Hernández-Ramírez, Araldi, Tatsi, Dale, Fridell, Mittal, Faucz, Iben, Li, Vitali, Stojilkovic, Kamenicky, Villa, Baussart, Chittiboina, Toro, Gahl, Eugster, Naves, Jaffrain-Rea, de Herder, Neggers, Petrossians, Beckers, Lania, Mains, Eipper and Stratakis |
| Copyright_xml | – notice: Copyright © 2023 Trivellin, Daly, Hernández-Ramírez, Araldi, Tatsi, Dale, Fridell, Mittal, Faucz, Iben, Li, Vitali, Stojilkovic, Kamenicky, Villa, Baussart, Chittiboina, Toro, Gahl, Eugster, Naves, Jaffrain-Rea, de Herder, Neggers, Petrossians, Beckers, Lania, Mains, Eipper and Stratakis. – notice: Distributed under a Creative Commons Attribution 4.0 International License – notice: Copyright © 2023 Trivellin, Daly, Hernández-Ramírez, Araldi, Tatsi, Dale, Fridell, Mittal, Faucz, Iben, Li, Vitali, Stojilkovic, Kamenicky, Villa, Baussart, Chittiboina, Toro, Gahl, Eugster, Naves, Jaffrain-Rea, de Herder, Neggers, Petrossians, Beckers, Lania, Mains, Eipper and Stratakis 2023 Trivellin, Daly, Hernández-Ramírez, Araldi, Tatsi, Dale, Fridell, Mittal, Faucz, Iben, Li, Vitali, Stojilkovic, Kamenicky, Villa, Baussart, Chittiboina, Toro, Gahl, Eugster, Naves, Jaffrain-Rea, de Herder, Neggers, Petrossians, Beckers, Lania, Mains, Eipper and Stratakis |
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| Keywords | 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 |
| Language | English |
| License | Copyright © 2023 Trivellin, Daly, Hernández-Ramírez, Araldi, Tatsi, Dale, Fridell, Mittal, Faucz, Iben, Li, Vitali, Stojilkovic, Kamenicky, Villa, Baussart, Chittiboina, Toro, Gahl, Eugster, Naves, Jaffrain-Rea, de Herder, Neggers, Petrossians, Beckers, Lania, Mains, Eipper and Stratakis. Distributed under a Creative Commons Attribution 4.0 International License: http://creativecommons.org/licenses/by/4.0 This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 scopus-id:2-s2.0-85163743083 ORCID: Giampaolo Trivellin, orcid.org/0000-0003-2384-4153; Chiara Villa, orcid.org/0000-0001-6245-4487 Reviewed by: Hironori Bando, Kobe University, Japan; Akira Shimatsu, Omi Medical Center, Japan Edited by: Hidenori Fukuoka, Kobe University, Japan |
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| PublicationTitle | Frontiers in endocrinology (Lausanne) |
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| Snippet | 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... IntroductionPituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause.... |
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| SubjectTerms | 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 |
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| Title | Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion |
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