NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice.

Autor: Chachlaki K; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience and Cognition, UMR-S 1172, Lille F-59000, France.; FHU 1000 Days for Health, School of Medicine, Lille F-59000, France.; Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland.; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland.; University Research Institute of Child Health and Precision Medicine, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, Athens 115 27, Greece., Messina A; Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland.; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland., Delli V; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience and Cognition, UMR-S 1172, Lille F-59000, France.; FHU 1000 Days for Health, School of Medicine, Lille F-59000, France., Leysen V; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience and Cognition, UMR-S 1172, Lille F-59000, France.; FHU 1000 Days for Health, School of Medicine, Lille F-59000, France., Maurnyi C; Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, 43 Szigony St., Budapest 1083, Hungary., Huber C; Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, Geneva 1211, Switzerland., Ternier G; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience and Cognition, UMR-S 1172, Lille F-59000, France.; FHU 1000 Days for Health, School of Medicine, Lille F-59000, France., Skrapits K; Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, 43 Szigony St., Budapest 1083, Hungary., Papadakis G; Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland.; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland., Shruti S; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience and Cognition, UMR-S 1172, Lille F-59000, France.; FHU 1000 Days for Health, School of Medicine, Lille F-59000, France., Kapanidou M; Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK., Cheng X; Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland.; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland., Acierno J; Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland.; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland., Rademaker J; Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland.; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland., Rasika S; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience and Cognition, UMR-S 1172, Lille F-59000, France.; FHU 1000 Days for Health, School of Medicine, Lille F-59000, France., Quinton R; Translational and Clinical Research Institute and the Royal Victoria Infirmary, University of Newcastle , Tyne NE1 3BZ, UK., Niedziela M; Department of Paediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, Poznan 61-701, Poland., L'Allemand D; Department of Endocrinology, Children's Hospital of Eastern Switzerland, St. Gallen 9000, Switzerland., Pignatelli D; Department of Endocrinology, Hospital S João; Department of Biomedicine, Faculty of Medicine of the University of Porto; IPATIMUP Research Institute, Porto 4200-319, Portugal., Dirlewander M; Pediatric Endocrine and Diabetes Unit, Children's Hospital, University Hospitals and Faculty of Medicine, Geneva CH1205, Switzerland., Lang-Muritano M; Division of Pediatric Endocrinology and Diabetology and Children's Research Centre, University Children's Hospital, Zürich 8032, Switzerland., Kempf P; Department of Diabetes, Endocrinology, Clinical Nutrition and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland., Catteau-Jonard S; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience and Cognition, UMR-S 1172, Lille F-59000, France.; FHU 1000 Days for Health, School of Medicine, Lille F-59000, France.; Department of Gynaecology and Obstretic, Jeanne de Flandres Hospital, Centre Hospitalier Universitaire de Lille, Lille F-59000, France., Niederländer NJ; Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland.; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland., Ciofi P; Inserm, U1215, Neurocentre Magendie, Université de Bordeaux, Bordeaux F-33077, France., Tena-Sempere M; Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba 14004, Spain.; Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC/HURS), Cordoba 14004, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Cordoba 14004, Spain., Garthwaite J; Wolfson Institute for Biomedical Research, University College London, London WC1E 6DH, UK., Storme L; FHU 1000 Days for Health, School of Medicine, Lille F-59000, France.; Department of Neonatology, Hôpital Jeanne de Flandre, CHU of Lille, Lille F-59000, France., Avan P; Université de Clerremont-Ferrand, Clermont-Ferrand F-63000, France., Hrabovszky E; Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, 43 Szigony St., Budapest 1083, Hungary., Carleton A; Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, Geneva 1211, Switzerland., Santoni F; Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland.; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland., Giacobini P; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience and Cognition, UMR-S 1172, Lille F-59000, France.; FHU 1000 Days for Health, School of Medicine, Lille F-59000, France., Pitteloud N; Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland.; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland., Prevot V; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience and Cognition, UMR-S 1172, Lille F-59000, France.; FHU 1000 Days for Health, School of Medicine, Lille F-59000, France.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2022 Oct 05; Vol. 14 (665), pp. eabh2369. Date of Electronic Publication: 2022 Oct 05.
DOI: 10.1126/scitranslmed.abh2369
Abstrakt: The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), which is crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. Whole-exome sequencing was performed on a cohort of 341 probands with congenital hypogonadotropic hypogonadism to identify ultrarare variants in NOS1 . The activity of the identified NOS1 mutant proteins was assessed by their ability to promote nitrite and cGMP production in vitro. In addition, physiological and pharmacological characterization was carried out in a Nos1 -deficient mouse model. We identified five heterozygous NOS1 loss-of-function mutations in six probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss, and intellectual disability. NOS1 was found to be transiently expressed by GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects in sexual maturation as well as in olfaction, hearing, and cognition. The pharmacological inhibition of NO production in postnatal mice revealed a critical time window during which Nos1 activity shaped minipuberty and sexual maturation. Inhaled NO treatment at minipuberty rescued both reproductive and behavioral phenotypes in Nos1 -deficient mice. In summary, lack of NOS1 activity led to GnRH deficiency associated with sensory and intellectual comorbidities in humans and mice. NO treatment during minipuberty reversed deficits in sexual maturation, olfaction, and cognition in Nos1 mutant mice, suggesting a potential therapy for humans with NO deficiency.
Databáze: MEDLINE
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