NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Science Translational Medicine Year : 2022

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

1 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
2 LilNCog - Lille Neurosciences & Cognition - U 1172
3 FHU 1 000 jours pour la santé
4 UNIL - Université de Lausanne = University of Lausanne
5 NKUA - National and Kapodistrian University of Athens
6 CHUV - Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
7 KOKI - Institute of Experimental Medicine [Budapest]
8 UNIGE - Université de Genève = University of Geneva
9 Oxford Brookes University
10 Newcastle University [Newcastle]
11 PUMS - Poznan University of Medical Sciences [Poland]
12 OST - University of Applied Sciences of Eastern Switzerland
13 Universidade do Porto = University of Porto
14 IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto
15 Geneva University Hospitals and Geneva University
16 University Children’s Hospital Zurich
17 Inselspital - Bern University Hospital [Berne]
18 UNIBE - Universität Bern / University of Bern
19 Hôpital Jeanne de Flandres
20 U1215 Inserm - UB - Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale
21 Universidad de Córdoba = University of Córdoba [Córdoba]
22 IMIBIC - Instituto Maimonides de Investigación Biomédica de Cordoba
23 ISC - Instituto de Salud Carlos III [Madrid]
24 UCL - University College of London [London]
25 WIBR - Wolfson Institute for Biomedical Research
26 METRICS - Evaluation des technologies de santé et des pratiques médicales - ULR 2694
27 Université de Clermont-Ferrand
Richard Quinton
Paul Avan


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.

Dates and versions

inserm-03841246 , version 1 (07-11-2022)



Konstantina Chachlaki, Andrea Messina, Virginia Delli, Valerie Leysen, Csilla Maurnyi, et al.. NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice. Science Translational Medicine, 2022, 14 (665), pp.eabh2369. ⟨10.1126/scitranslmed.abh2369⟩. ⟨inserm-03841246⟩
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