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

Konstantina Chachlaki (1, 2, 3, 4, 5, 6) , Andrea Messina (4, 6) , Virginia Delli (1, 2, 3) , Valerie Leysen (1, 2, 3) , Csilla Maurnyi (7) , Chieko Huber (8) , Gaëtan Ternier (1, 2, 3) , Katalin Skrapits (7) , Georgios Papadakis (4, 6) , Sonal Shruti (1, 2, 3) , Maria Kapanidou (9) , Xu Cheng (4, 6) , James Acierno (4, 6) , Jesse Rademaker (4, 6) , Sowmyalakshmi Rasika (1, 2, 3) , Richard Quinton (10) , Marek Niedziela (11) , Dagmar L’allemand (12) , Duarte Pignatelli (13, 14) , Mirjam Dirlewander (15) , Mariarosaria Lang-Muritano (16) , Patrick Kempf (17, 18) , Sophie Catteau-Jonard (1, 2, 3, 19) , Nicolas Niederländer (4, 6) , Philippe Ciofi (20) , Manuel Tena-Sempere (21, 22, 23) , John Garthwaite (24, 25) , Laurent Storme (3, 19) , Paul Avan (26) , Erik Hrabovszky (7) , Alan Carleton (8) , Federico Santoni (4, 6) , Paolo Giacobini (1, 2, 3) , Nelly Pitteloud (4, 6) , Vincent Prevot (2, 1, 3)
1 CHU Lille
2 LilNCog - Lille Neurosciences & Cognition - U 1172
3 FHU 1,000 Days for Health [Lille]
4 UNIL - Université de Lausanne = University of Lausanne
5 NKUA - National and Kapodistrian University of Athens
6 Lausanne University Hospital
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 FHO - 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 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 Université de Clermont-Ferrand
Konstantina Chachlaki
CHU Lille
Lille Neurosciences & Cognition - U 1172
FHU 1,000 Days for Health [Lille]
Université de Lausanne = University of Lausanne
National and Kapodistrian University of Athens
Lausanne University Hospital
Andrea Messina
Université de Lausanne = University of Lausanne
Lausanne University Hospital
Virginia Delli
CHU Lille
Lille Neurosciences & Cognition - U 1172
FHU 1,000 Days for Health [Lille]
Valerie Leysen
  • Function : Author
CHU Lille
Lille Neurosciences & Cognition - U 1172
FHU 1,000 Days for Health [Lille]
Csilla Maurnyi
  • Function : Author
Institute of Experimental Medicine [Budapest]
Chieko Huber
Université de Genève = University of Geneva
Gaëtan Ternier
CHU Lille
Lille Neurosciences & Cognition - U 1172
FHU 1,000 Days for Health [Lille]
Katalin Skrapits
  • Function : Author
Institute of Experimental Medicine [Budapest]
Georgios Papadakis
Université de Lausanne = University of Lausanne
Lausanne University Hospital
Sonal Shruti
CHU Lille
Lille Neurosciences & Cognition - U 1172
FHU 1,000 Days for Health [Lille]
Maria Kapanidou
  • Function : Author
Oxford Brookes University
Xu Cheng
Université de Lausanne = University of Lausanne
Lausanne University Hospital
James Acierno
  • Function : Author
Université de Lausanne = University of Lausanne
Lausanne University Hospital
Jesse Rademaker
Université de Lausanne = University of Lausanne
Lausanne University Hospital
Sowmyalakshmi Rasika
CHU Lille
Lille Neurosciences & Cognition - U 1172
FHU 1,000 Days for Health [Lille]
Richard Quinton
Newcastle University [Newcastle]
Marek Niedziela
Poznan University of Medical Sciences [Poland]
Dagmar L’allemand
University of Applied Sciences of Eastern Switzerland
Duarte Pignatelli
Universidade do Porto = University of Porto
Instituto de Patologia e Imunologia Molecular da Universidade do Porto
Mirjam Dirlewander
  • Function : Author
Geneva University Hospitals and Geneva University
Mariarosaria Lang-Muritano
  • Function : Author
University Children’s Hospital Zurich
Patrick Kempf
  • Function : Author
Bern University Hospital [Berne]
University of Bern
Sophie Catteau-Jonard
CHU Lille
Lille Neurosciences & Cognition - U 1172
FHU 1,000 Days for Health [Lille]
Hôpital Jeanne de Flandres
Nicolas Niederländer
  • Function : Author
Université de Lausanne = University of Lausanne
Lausanne University Hospital
Philippe Ciofi
  • Function : Author
Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale
Manuel Tena-Sempere
Universidad de Córdoba = University of Córdoba [Córdoba]
Instituto Maimonides de Investigación Biomédica de Cordoba
Instituto de Salud Carlos III [Madrid]
John Garthwaite
University College of London [London]
Wolfson Institute for Biomedical Research
Laurent Storme
  • Function : Author
FHU 1,000 Days for Health [Lille]
Hôpital Jeanne de Flandres
Paul Avan
Université de Clermont-Ferrand
Erik Hrabovszky
Institute of Experimental Medicine [Budapest]
Alan Carleton
Université de Genève = University of Geneva
Federico Santoni
Université de Lausanne = University of Lausanne
Lausanne University Hospital
Paolo Giacobini
CHU Lille
Lille Neurosciences & Cognition - U 1172
FHU 1,000 Days for Health [Lille]
Nelly Pitteloud
Connectez-vous pour contacter l'auteur
Université de Lausanne = University of Lausanne
Lausanne University Hospital
Vincent Prevot
  • Function : Correspondent author
  • PersonId : 857771

Connectez-vous pour contacter l'auteur
Lille Neurosciences & Cognition - U 1172
CHU Lille
FHU 1,000 Days for Health [Lille]

Abstract

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.

Domains

Neurons and Cognition [q-bio.NC]

Vincent Prevot  : Connect in order to contact the contributor

https://www.hal.inserm.fr/inserm-03841246

Submitted on : Monday, November 7, 2022-7:29:26 AM

Last modification on : Wednesday, February 15, 2023-3:09:57 PM

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

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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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