NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice
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Andrea Messina
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- ORCID : 0000-0002-2393-1874
Virginia Delli
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- ORCID : 0000-0001-9137-8735
Chieko Huber
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Gaëtan Ternier
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Georgios Papadakis
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Sonal Shruti
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Xu Cheng
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- ORCID : 0000-0002-2488-4424
Jesse Rademaker
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- ORCID : 0000-0003-3961-3333
Sowmyalakshmi Rasika
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- ORCID : 0000-0001-8733-4641
Richard Quinton
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- ORCID : 0000-0002-4842-8095
Marek Niedziela
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- ORCID : 0000-0001-8862-6937
Dagmar L’allemand
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- ORCID : 0000-0003-3144-3907
Duarte Pignatelli
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- ORCID : 0000-0002-5555-7004
Sophie Catteau-Jonard
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- ORCID : 0000-0003-1285-6423
Manuel Tena-Sempere
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- ORCID : 0000-0002-4741-5567
John Garthwaite
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- ORCID : 0000-0003-1970-8095
Paul Avan
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- ORCID : 0000-0003-1054-1479
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Erik Hrabovszky
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- ORCID : 0000-0001-6927-0015
Alan Carleton
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- ORCID : 0000-0001-5633-9159
Federico Santoni
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- ORCID : 0000-0002-3258-4747
Paolo Giacobini
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- ORCID : 0000-0002-3075-1441
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Nelly Pitteloud
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- Function : Correspondent author
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- ORCID : 0000-0003-0971-3237
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Vincent Prevot
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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.