Leyla Akin1, Karine Rizzoti2, Louise C Gregory3, Beatriz Corredor4, Polona Le Quesne Stabej5, Hywel Williams6, Federica Buonocore3, Stephane Mouilleron7, Valeria Capra8, Sinead M McGlacken-Byrne3, Gabriel Á Martos-Moreno9, Dimitar N Azmanov10, Mustafa Kendirci11, Selim Kurtoglu11, Jenifer P Suntharalingham3, Christophe Galichet2, Stefano Gustincich12, Velibor Tasic13, John C Achermann3, Andrea Accogli14, Aleksandra Filipovska15, Anatoly Tuilpakov16, Mohamad Maghnie17, Zoran Gucev13, Zeynep Burcin Gonen18, Luis A Pérez-Jurado19, Iain Robinson2, Robin Lovell-Badge2, Jesús Argente20, Mehul T Dattani21. 1. Department of Paediatric Endocrinology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey; Department of Paediatric Endocrinology, Faculty of Medicine, Erciyes University, Kayseri, Turkey. Electronic address: leylabakin@gmail.com. 2. Stem Cell Biology and Developmental Genetics Lab, The Francis Crick Institute, London, United Kingdom. 3. Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom. 4. Departments of Paediatrics and Paediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain. 5. GOSgene, Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand. 6. Division of Cancer and Genetics, Genetics and Genomic Medicine, School of Medicine, Cardiff University, Cardiff, United Kingdom. 7. Structural Biology Science Technology Platforms, The Francis Crick Institute, London, United Kingdom. 8. Unit of Medical Genetics, IRCCS Giannina Gaslini Institute, Genova, Italy. 9. Departments of Paediatrics and Paediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; Department of Paediatrics, Universidad Autónoma de Madrid, Madrid, Spain; CIBER Fisiopatología Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain. 10. Centre of Medical Research, The University of Western Australia and Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia; Department of Diagnostic Genomics, PathWest, QEII MedicalCentre, Perth, Western Australia, Australia. 11. Department of Paediatric Endocrinology, Faculty of Medicine, Erciyes University, Kayseri, Turkey. 12. Istituto Italiano di Tecnologia - IIT, Genova, Italy. 13. University Children's Hospital, Medical School, Skopje, North Macedonia. 14. Division of Medical Genetics, Department of Specialized Medicine, Montreal Children's Hospital, McGill University Health Centre (MUHC), Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada. 15. Centre of Medical Research, The University of Western Australia and Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia; Telethon Kids Institute, Perth Children's Hospital, Nedlands, Western Australia, Australia. 16. Department of Endocrine Genetics, Research Centre for Medical Genetics, Moscow, Russia; Department of Inherited Endocrine Disorders, Endocrinology Research Centre, Moscow, Russia. 17. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy; Department of Paediatrics, IRCCS Giannina Gaslini Institute, Genoa, Italy. 18. Oral and Maxillofacial Surgery, Genome and Stem Cell Center, Erciyes University, Kayseri, Turkey. 19. Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain; South Australian Health and Medical Research Institute (SAHMRI), The University of Adelaide, Adelaide, South Australia, Australia. 20. Departments of Paediatrics and Paediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; Department of Paediatrics, Universidad Autónoma de Madrid, Madrid, Spain; CIBER Fisiopatología Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain; IMDEA Food Institute, Campus of International Excellence UAM+CSIC, Madrid, Spain. 21. Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; South Australian Health and Medical Research Institute (SAHMRI), The University of Adelaide, Adelaide, South Australia, Australia; Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, United Kingdom. Electronic address: m.dattani@ucl.ac.uk.
Abstract
PURPOSE: We aimed to investigate the molecular basis underlying a novel phenotype including hypopituitarism associated with primary ovarian insufficiency. METHODS: We used next-generation sequencing to identify variants in all pedigrees. Expression of Rnpc3/RNPC3 was analyzed by in situ hybridization on murine/human embryonic sections. CRISPR/Cas9 was used to generate mice carrying the p.Leu483Phe pathogenic variant in the conserved murine Rnpc3 RRM2 domain. RESULTS: We described 15 patients from 9 pedigrees with biallelic pathogenic variants in RNPC3, encoding a specific protein component of the minor spliceosome, which is associated with a hypopituitary phenotype, including severe growth hormone (GH) deficiency, hypoprolactinemia, variable thyrotropin (also known as thyroid-stimulating hormone) deficiency, and anterior pituitary hypoplasia. Primary ovarian insufficiency was diagnosed in 8 of 9 affected females, whereas males had normal gonadal function. In addition, 2 affected males displayed normal growth when off GH treatment despite severe biochemical GH deficiency. In both mouse and human embryos, Rnpc3/RNPC3 was expressed in the developing forebrain, including the hypothalamus and Rathke's pouch. Female Rnpc3 mutant mice displayed a reduction in pituitary GH content but with no reproductive impairment in young mice. Male mice exhibited no obvious phenotype. CONCLUSION: Our findings suggest novel insights into the role of RNPC3 in female-specific gonadal function and emphasize a critical role for the minor spliceosome in pituitary and ovarian development and function.
PURPOSE: We aimed to investigate the molecular basis underlying a novel phenotype including hypopituitarism associated with primary ovarian insufficiency. METHODS: We used next-generation sequencing to identify variants in all pedigrees. Expression of Rnpc3/RNPC3 was analyzed by in situ hybridization on murine/human embryonic sections. CRISPR/Cas9 was used to generate mice carrying the p.Leu483Phe pathogenic variant in the conserved murine Rnpc3 RRM2 domain. RESULTS: We described 15 patients from 9 pedigrees with biallelic pathogenic variants in RNPC3, encoding a specific protein component of the minor spliceosome, which is associated with a hypopituitary phenotype, including severe growth hormone (GH) deficiency, hypoprolactinemia, variable thyrotropin (also known as thyroid-stimulating hormone) deficiency, and anterior pituitary hypoplasia. Primary ovarian insufficiency was diagnosed in 8 of 9 affected females, whereas males had normal gonadal function. In addition, 2 affected males displayed normal growth when off GH treatment despite severe biochemical GH deficiency. In both mouse and human embryos, Rnpc3/RNPC3 was expressed in the developing forebrain, including the hypothalamus and Rathke's pouch. Female Rnpc3 mutant mice displayed a reduction in pituitary GH content but with no reproductive impairment in young mice. Male mice exhibited no obvious phenotype. CONCLUSION: Our findings suggest novel insights into the role of RNPC3 in female-specific gonadal function and emphasize a critical role for the minor spliceosome in pituitary and ovarian development and function.
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