Dataset related to article "Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion"
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Giampaolo Trivellin1
- Adrian F. Daly2
- Laura C. Hernández-Ramírez3
- Elisa Araldi4
- Christina Tatsi5
- Ryan K. Dale6
- Gus Fridell6
- Arjun Mittal6
- Fabio R. Faucz7
- James R. Iben8
- Tianwei Li8
- Eleonora Vitali9
- Stanko S. Stojilkovic10
- Peter Kamenicky11
- Chiara Villa12
- Bertrand Baussart13
- Prashant Chittiboina14
- Camilo Toro15
- William A. Gahl15
- Erica A. Eugster16
- Luciana A. Naves17
- Marie-Lise Jaffrain-Rea18
- Wouter W. de Herder19
- Sebastian JCMM Neggers20
- Patrick Petrossians2
- Albert Beckers2
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Andrea G. Lania1
- Richard E. Mains21
- Betty A. Eipper22
- Constantine A. Stratakis23
- 1. IRCCS Humanitas Research Hospital, via Manzoni 56,20089 Rozzano (Mi) - Italy AND Humanitas University, Department of Biomedical Sciences, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele – Milan, Italy
- 2. Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium
- 3. 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. Tlalpan, CDMX 14080, Mexico AND Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA
- 4. Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, CH-8603, Switzerland
- 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 20892, USA
- 6. Bioinformatics and Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA
- 7. Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA AND Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
- 8. Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
- 9. IRCCS Humanitas Research Hospital, via Manzoni 56, 20072 Rozzano (Mi) - Italy
- 10. Section on Cellular Signaling, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA
- 11. Universite Paris-Saclay, INSERM, Physiologie et Physiopathologie Endocriniennes, 94270 Le Kremlin-Bicetre, France
- 12. Departement de Neuropathologie de la Pitie Salpetriere, Hopital de la Pitie-Salpetriere - APHP Sorbonne Universite, 47-83 Bd de l'Hopital 75651, Paris, France AND INSERM U1016, CNRS UMR 8104, Institut Cochin, 75014 Paris, France
- 13. INSERM U1016, CNRS UMR 8104, Institut Cochin, 75014 Paris, France AND Service de Neurochirurgie, Hopital Pitie-Salpetriere, AP-HP Sorbonne, 47-83 Boulevard de l'Hopital, 75651 Paris, France
- 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 20892, USA
- 15. NIH Undiagnosed Diseases Program, Office of the Clinical Director, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA
- 16. Division of Endocrinology & Diabetes, Department of Pediatrics, Riley Hospital for Children at IU Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- 17. Service of Endocrinology, University Hospital, Faculty of Medicine, University of Brasilia, 70910900 Brasilia, Brazil
- 18. Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy AND Neuromed Institute, Istituto di Ricovero e Cura a Carattere Scientifico, 86077 Pozzilli, Italy
- 19. Department of Medicine, Section Endocrinology, Pituitary Center Rotterdam, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands
- 20. Sebastian JCMM Neggers
- 21. Department of Neuroscience, UConn Health, 263 Farmington 56 Avenue, Farmington, CT 06030, USA
- 22. Department of Molecular Biology and Biophysics, UConn Health, 263 Farmington Avenue, Farmington, CT 06030, USA
- 23. Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA AND Human Genetics & Precision Medicine, IMBB, Foundation for Research & Technology Hellas, 70013 Heraklion, Crete, Greece AND Research Institute, ELPEN, Pikermi, 19009 Athens, Greece
Description
This record contains raw data related to article "Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion"
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 to 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.
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