Reassessing the role of the p.(Arg304Gln) missense AIP variant in pituitary tumorigenesis.
Mary N Dang, Alessia David, Anne Barlier, Philippe Chanson, Ashley B Grossman, Paul Benjamin Loughrey, Nadira B Mothojakan, Ankit Arni, Elena D Aflorei, Mariana F Bizzi, Jakob Dal, Márta Korbonits, Amy Evans, Sonal Kapur, Chandan Kumar-Sinha, Ronald M Lechan, Mark Ludman, Vishnou Mourougavelou, Martina Owens, Ionela Pascanu, Sergio V B Pinheiro, Antonio Ribeiro-Oliveira, Serban Radian, Francesco Ferrau, Matheus de Oliveira Andrade, Monica R Gadelha, Donato Iacovazzo, Daniel Flanagan, Louise A Metherell, Bernard Khoo, Albert Beckers, Kashyap A Patel, Christof Schöfl, Adrian F Daly, Madalina Musat, Ajith V Kumar, Dragana Miljic, Tobias Else, Gianluca Occhi, Giorgio Arnaldi, Laura C Hernández-Ramírez, Marianne S Elston, Simona Fica
Journal: European journal of endocrinology
2025;192(4):385-397
PMID: 40070360
Abstract
OBJECTIVE
Heterozygous germline loss-of-function variants in AIP are associated with young-onset growth hormone and/or prolactin-secreting pituitary tumours. However, the pathogenic role of the c.911G > A; p.(Arg304Gln) (R304Q) AIP variant has been controversial. Recent data from public exome/genome databases show this variant is not infrequent. The objective of this work was to reassess the pathogenicity of R304Q based on clinical, genomic, and functional assay data.
DESIGN
Data were collected on published R304Q pituitary neuroendocrine tumour cases and from International Familial Isolated Pituitary Adenoma Consortium R304Q cases (n = 38, R304Q cohort). Clinical features, population cohort frequency, computational analyses, prediction models, presence of loss-of-heterozygosity, and in vitro/in vivo functional studies were assessed and compared with data from pathogenic/likely pathogenic AIP variant patients (AIPmut cohort, n = 184).
RESULTS
Of 38 R304Q patients, 61% (23/38) had growth hormone excess, in contrast to 80% of AIPmut cohort (147/184, P < .001). R304Q cohort was older at disease onset and diagnosis than the AIPmut cohort (median [quartiles] onset: 25 y [16-35] vs 16 y [14-23], P < .001; median [quartiles] diagnosis: 36 y [24-44] vs 21 y [15-29], P < .001). R304Q is present in gnomADv2.1 (0.31%) and UK Biobank (0.16%), including three persons with homozygous R304Q. No loss-of-heterozygosity was detected in four R304Q pituitary neuroendocrine tumour samples. In silico predictions and experimental data were conflicting.
CONCLUSIONS
Evidence suggests that R304Q is not pathogenic for pituitary neuroendocrine tumour. We recommend changing this variant classification to likely benign and do not recommend pre-symptomatic genetic testing of family members or follow-up of already identified unaffected individuals with the R304Q variant.
© The Author(s) 2025. Published by Oxford University Press on behalf of European Society of Endocrinology.
Address:
Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom.; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE, United Kingdom.; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom.; Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, EX1 2HZ, United Kingdom.; Section of Endocrinology, PROMISE, University of Palermo, Palermo 90127, Italy.; Unità Operativa Complessa of Endocrine Diseases, A.O.U.P. Paolo Giaccone of Palermo, Palermo 90127, Italy.; Aix Marseille Univ APHM, INSERM, UMR1251 MMG, Laboratory of Molecular Biology GEnOPé, Biogénopôle, Hôpital de la Timone, Marseille 13385, France.; Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Liège 4000, Belgium.; Department of Internal Medicine, Federal University of Minas Gerais, Belo Horizonte/Minas Gerais, 30130-100, Brazil.; Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, Le Kremlin-Bicêtre, 94275, France.; Department of Endocrinology, Aalborg University Hospital, Aalborg 9000, Denmark.; Centre for Bioinformatics, Department of Life Sciences, Imperial College London, London, SW7 2AZ, United Kingdom.; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom.; Faculty of Medicine, University of Brasilia, Brasilia 70910-900, Brazil.; MEND/Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, United States.; Waikato Clinical Campus, The University of Auckland, Hamilton 3216, New Zealand.; Department of Human Pathology of Adulthood and Childhood 'G. Barresi', University of Messina, Messina 98125, Italy.; Endocrinology and Diabetes Department, Elias Hospital, University of Medicine and Pharmacy Carol Davila Bucharest, Bucharest 011461, Romania.; Department of Endocrinology, University Hospitals Plymouth NHS Trust, Plymouth, PL6 8DH, United Kingdom.; Endocrinology Unit, Department of Internal Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-853, Brazil.; Division of Medicine, University College London, Royal Free Campus, London, NW3 2PS, United Kingdom.; North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London, WC1N 3BH, United Kingdom.; Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0940, United States.; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, MA 02111, United States.; Institute of Genetics, Meir Medical Center, Kfar Saba, 4428164, Israel.; Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Center of Serbia, Belgrade 11000, Serbia.; Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia.; National Institute of Endocrinology, University of Medicine and Pharmacy Carol Davila Bucharest, Bucharest 050474, Romania.; Department of Biology, University of Padua, Padua 35128, Italy.; Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, EX2 5DW, United Kingdom.; Department of Endocrinology, George Emil Palade University of Medicine Pharmacy Science and Technology of Targu Mures, Targu Mures 540139, Romania.; Department of Pediatrics, Federal University of Minas Gerais, Belo Horizonte/Minas Gerais 30130-100, Brazil.; Center of Endocrinology and Metabolism, Bamberg and Erlangen, Obstmarkt 1, Bamberg 96047, Germany.; Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom.; 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, México City 14080, Mexico.
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MeSH Terms:
Humans,
Female,
Male,
Mutation, Missense,
Adult,
Middle Aged,
Pituitary Neoplasms,
Growth Hormone-Secreting Pituitary Adenoma,
Carcinogenesis,
Cohort Studies,
Intracellular Signaling Peptides and Proteins,
Adenoma,
Young Adult
