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 Accéder directement au contenu
Article Dans Une Revue Science Translational Medicine Année : 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, 26) , Paul Avan (27) , 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 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
Konstantina Chachlaki
Centre Hospitalier Régional Universitaire [CHU Lille]
Lille Neurosciences & Cognition - U 1172
FHU 1 000 jours pour la santé
Université de Lausanne = University of Lausanne
National and Kapodistrian University of Athens
Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
Andrea Messina
Université de Lausanne = University of Lausanne
Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
Virginia Delli
Centre Hospitalier Régional Universitaire [CHU Lille]
Lille Neurosciences & Cognition - U 1172
FHU 1 000 jours pour la santé
Valerie Leysen
  • Fonction : Auteur
Centre Hospitalier Régional Universitaire [CHU Lille]
Lille Neurosciences & Cognition - U 1172
FHU 1 000 jours pour la santé
Csilla Maurnyi
  • Fonction : Auteur
Institute of Experimental Medicine [Budapest]
Chieko Huber
Université de Genève = University of Geneva
Gaëtan Ternier
Centre Hospitalier Régional Universitaire [CHU Lille]
Lille Neurosciences & Cognition - U 1172
FHU 1 000 jours pour la santé
Katalin Skrapits
  • Fonction : Auteur
Institute of Experimental Medicine [Budapest]
Georgios Papadakis
Université de Lausanne = University of Lausanne
Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
Sonal Shruti
Centre Hospitalier Régional Universitaire [CHU Lille]
Lille Neurosciences & Cognition - U 1172
FHU 1 000 jours pour la santé
Maria Kapanidou
  • Fonction : Auteur
Oxford Brookes University
Xu Cheng
Université de Lausanne = University of Lausanne
Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
James Acierno
  • Fonction : Auteur
Université de Lausanne = University of Lausanne
Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
Jesse Rademaker
Université de Lausanne = University of Lausanne
Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
Sowmyalakshmi Rasika
Centre Hospitalier Régional Universitaire [CHU Lille]
Lille Neurosciences & Cognition - U 1172
FHU 1 000 jours pour la santé
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
  • Fonction : Auteur
Geneva University Hospitals and Geneva University
Mariarosaria Lang-Muritano
  • Fonction : Auteur
University Children’s Hospital Zurich
Patrick Kempf
  • Fonction : Auteur
Bern University Hospital [Berne]
Universität Bern / University of Bern
Sophie Catteau-Jonard
Centre Hospitalier Régional Universitaire [CHU Lille]
Lille Neurosciences & Cognition - U 1172
FHU 1 000 jours pour la santé
Hôpital Jeanne de Flandres
Nicolas Niederländer
  • Fonction : Auteur
Université de Lausanne = University of Lausanne
Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
Philippe Ciofi
  • Fonction : Auteur
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
  • Fonction : Auteur
FHU 1 000 jours pour la santé
Hôpital Jeanne de Flandres
Evaluation des technologies de santé et des pratiques médicales - ULR 2694
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
Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
Paolo Giacobini
Centre Hospitalier Régional Universitaire [CHU Lille]
Lille Neurosciences & Cognition - U 1172
FHU 1 000 jours pour la santé
Nelly Pitteloud
Connectez-vous pour contacter l'auteur
Université de Lausanne = University of Lausanne
Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
Vincent Prevot
  • Fonction : Auteur correspondant
  • PersonId : 857771

Connectez-vous pour contacter l'auteur
Lille Neurosciences & Cognition - U 1172
Centre Hospitalier Régional Universitaire [CHU Lille]
FHU 1 000 jours pour la santé

Résumé

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.

Domaines

Neurosciences [q-bio.NC]

Vincent Prevot  : Connectez-vous pour contacter le contributeur

https://inserm.hal.science/inserm-03841246

Soumis le : lundi 7 novembre 2022-07:29:26

Dernière modification le : vendredi 19 avril 2024-14:04:05

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Dates et versions

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

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Citer

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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