RT Journal Article
T1 NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice.
A1 Chachlaki, Konstantina
A1 Messina, Andrea
A1 Delli, Virginia
A1 Leysen, Valerie
A1 Maurnyi, Csilla
A1 Huber, Chieko
A1 Ternier, Gaëtan
A1 Skrapits, Katalin
A1 Papadakis, Georgios
A1 Shruti, Sonal
A1 Kapanidou, Maria
A1 Cheng, Xu
A1 Acierno, James
A1 Rademaker, Jesse
A1 Rasika, Sowmyalakshmi
A1 Quinton, Richard
A1 Niedziela, Marek
A1 L'Allemand, Dagmar
A1 Pignatelli, Duarte
A1 Dirlewander, Mirjam
A1 Lang-Muritano, Mariarosaria
A1 Kempf, Patrick
A1 Catteau-Jonard, Sophie
A1 Niederländer, Nicolas J
A1 Ciofi, Philippe
A1 Tena-Sempere, Manuel
A1 Garthwaite, John
A1 Storme, Laurent
A1 Avan, Paul
A1 Hrabovszky, Erik
A1 Carleton, Alan
A1 Santoni, Federico
A1 Giacobini, Paolo
A1 Pitteloud, Nelly
A1 Prevot, Vincent
K1 Mutant Proteins
K1 Mutation
K1 Nitric Oxide
K1 Nitric Oxide Synthase Type I
K1 Nitrites
AB 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.
PB American Association for the Advancement of Science (AAAS)
YR 2022
FD 2022-10-05
LK http://hdl.handle.net/10668/20031
UL http://hdl.handle.net/10668/20031
LA en
NO Chachlaki K, Messina A, Delli V, Leysen V, Maurnyi C, Huber C, et al. NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice. Sci Transl Med. 2022 Oct 5;14(665):eabh2369
NO This work has been supported bythe European Union Horizon 2020 research and innovation program no. 847941 miniNO (to K.C.,L.S., A.C., F.S. N.P., and V.P.), the European Research Council COST action BM1105 for the studyof GnRH deficiency (to N.P., V.P., P.G., R.Q., M.N., D.L.A., D.P., E.H., M.T.-S., and P.C.) and theproject no. 874741 HUGODECA (to P.G.), the Fondation pour la Recherche Médicale (EquipeFRM, DEQ20130326524 to V.P and SPE201803005208 to K.C.), the Agence Nationale de laRecherche (ANR-17-CE16-0015 to V.P. and P.C.), Inserm Cross-Cutting Scientific Program(HuDeCA to P.G.), the Swiss National Foundation grants 310030_173260 (to N.P.) and310030_185292 (to F.S.), Novartis Foundation (18O52 to F.S.), the Hungarian Brain ResearchProgram (2017-1.2.1-NKP-2017-00002 to E.H.), and Hungarian Scientific Research Fund(K128317 and K138137 to E.H. and PD134837 to K.S).
DS RISalud
RD Apr 8, 2025