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
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
Andrea Messina
- Function : Author
- PersonId : 1165220
- ORCID : 0000-0002-2393-1874
Virginia Delli
- Function : Author
- PersonId : 1182638
- ORCID : 0000-0001-9137-8735
Chieko Huber
- Function : Author
- PersonId : 1182639
- ORCID : 0000-0003-0847-0181
Gaëtan Ternier
- Function : Author
- PersonId : 1182640
- ORCID : 0000-0002-0004-1457
Georgios Papadakis
- Function : Author
- PersonId : 1182641
- ORCID : 0000-0002-0099-6755
Sonal Shruti
- Function : Author
- PersonId : 1182642
- ORCID : 0000-0003-3772-1939
Xu Cheng
- Function : Author
- PersonId : 1182643
- ORCID : 0000-0002-2488-4424
Jesse Rademaker
- Function : Author
- PersonId : 1182644
- ORCID : 0000-0003-3961-3333
Sowmyalakshmi Rasika
- Function : Author
- PersonId : 806729
- ORCID : 0000-0001-8733-4641
Richard Quinton
- Function : Author
- PersonId : 1182645
- ORCID : 0000-0002-4842-8095
Marek Niedziela
- Function : Author
- PersonId : 1182646
- ORCID : 0000-0001-8862-6937
Dagmar L’allemand
- Function : Author
- PersonId : 1182647
- ORCID : 0000-0003-3144-3907
Duarte Pignatelli
- Function : Author
- PersonId : 1182648
- ORCID : 0000-0002-5555-7004
Sophie Catteau-Jonard
- Function : Author
- PersonId : 1182649
- ORCID : 0000-0003-1285-6423
Manuel Tena-Sempere
- Function : Author
- PersonId : 1165212
- ORCID : 0000-0002-4741-5567
John Garthwaite
- Function : Author
- PersonId : 1182650
- ORCID : 0000-0003-1970-8095
Paul Avan
- Function : Author
- PersonId : 757299
- ORCID : 0000-0003-1054-1479
- IdRef : 034318135
Erik Hrabovszky
- Function : Author
- PersonId : 1182651
- ORCID : 0000-0001-6927-0015
Alan Carleton
- Function : Author
- PersonId : 757494
- ORCID : 0000-0001-5633-9159
Federico Santoni
- Function : Author
- PersonId : 1165218
- ORCID : 0000-0002-3258-4747
Paolo Giacobini
- Function : Author
- PersonId : 767534
- ORCID : 0000-0002-3075-1441
- IdRef : 182894541
Nelly Pitteloud
Connectez-vous pour contacter l'auteur
- Function : Correspondent author
- PersonId : 1165221
- ORCID : 0000-0003-0971-3237
Connectez-vous pour contacter l'auteur
Vincent Prevot
Connectez-vous pour contacter l'auteur
- Function : Correspondent author
- PersonId : 857771
Connectez-vous pour contacter l'auteur
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.