ESPEYB20 5. Puberty Basic Research (6 abstracts)
5.13. NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice
Chachlaki K , Messina A , Delli V , Leysen V , Maurnyi C , Huber C , Ternier G , Skrapits K , Papadakis G , Shruti S , Kapanidou M , Cheng X , Acierno J , Rademaker J , Rasika S , Quinton R , Niedziela M , L’Allemand D , Pignatelli D , Dirlewander M , Lang-Muritano M , Kempf P , Catteau-Jonard S , Niederländer NJ , Ciofi P , Tena-Sempere M , Garthwaite J , Storme L , Avan P , Hrabovszky E , Carleton A , Santoni F , Giacobini P , Pitteloud N & Prevot V
Sci Transl Med. 2022;14(665):eabh2369.PMID: 36197968. https://www.science.org/doi/10.1126/scitranslmed.abh2369?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
Brief summary: This study identified nitric oxide synthase 1 (NOS1) heterozygous missense variants in 6 patients with hypogonadotropic hypogonadism. Altered minipuberty and puberty as well as cognitive impairment were observed in NOS1 deficient mice.
Nitric oxide (NO) is produced under the control of NO synthase in hypothalamic neurons. NO plays a crucial role in regulating gonadotropin-releasing hormone (GnRH) secretion, acting as a strong inhibitory signal which integrates both metabolic and gonadal information (1). Nos1 (NO synthase 1) deficient mice exhibit infertility, which suggests that NOS1 loss-of-function mutations could lead to GnRH deficiency and infertility due to congenital hypogonadotropic hypogonadism (CHH).
This study identified 6 ultra-rare NOS1 missense variants among a cohort of 341 patients with CHH. All affected patients had absent puberty, suggesting severe GnRH deficiency. In vitro characterization of the mutants confirmed they resulted in NOS1 loss-of-function.
Immunohistology showed that NOS1 is expressed in some migrating GnRH neurons in humans. In adults, GnRH neurons interacted morphologically with NOS1 neurons but did not themselves express NOS1. Some kisspeptin neurons expressed NOS1.
NOS1 deficient mice showed increased firing of GnRH neurons around minipuberty together with increased LH and FSH levels and further showed delayed puberty. They also showed impaired hearing, olfaction and cognition, which is consistent with the hearing loss, anosmia and cognitive difficulties reported in patients with NOS1 mutations. Notably, both reproductive and cognitive phenotypes were corrected by inhaled NO treatment in mice.
In conclusion, this very elegant study shows that Nos1 activity shapes minipuberty and puberty, and also plays a role in cognition. Notably, it also suggests a potential therapeutic application for inhaled NO.
Reference: 1. Chachlaki K, Garthwaite J, Prevot V. The gentle art of saying NO: how nitric oxide gets things done in the hypothalamus. Nat Rev Endocrinol. 2017;13:521–535. [PubMed: 28621341]
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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