JOM KITA KE POLITEKNIK

NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits: reversal with NO therapy in infantile mice (Record no. 1702)

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Personal name Chachlaki, Konstantina
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9 (RLIN) 1494
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Title NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits: reversal with NO therapy in infantile mice
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Date of publication, distribution, etc. 2022-10-05.
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General note /pmc/articles/PMC7613826/
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General note /pubmed/36197968
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Summary, etc. BACKGROUND: The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. METHODS: Whole exome sequencing was performed on a large cohort of probands with congenital hypogonadotropic hypogonadism to identify ultra-rare variants in NOS1. The activity of NOS1 mutants identified 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. FINDINGS: We identified 5 heterozygous NOS1 loss-of-function mutations in 6 probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss and intellectual disability. In addition, NOS1 was found to be transiently expressed by newly born GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects not only in sexual maturation but also olfaction, hearing and cognition. The pharmacological inhibition of NO production in infantile 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. INTERPRETATION: The lack of timely NOS1 activity causes GnRH deficiency and lifelong sensory and intellectual comorbidities in humans and mice. NO treatment during a critical window, by reversing deficits in sexual maturation, olfaction and cognition in Nos1-deficient mice, thus holds therapeutic potential for humans.
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Personal name Messina, Andrea
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Personal name Delli, Virginia
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9 (RLIN) 1496
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Personal name Leysen, Valerie
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Personal name Maurnyi, Csilla
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9 (RLIN) 1498
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Personal name Huber, Chieko
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9 (RLIN) 1499
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Personal name Ternier, Gaëtan
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9 (RLIN) 1500
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Personal name Skrapits, Katalin
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9 (RLIN) 1501
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Personal name Papadakis, Georgios
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9 (RLIN) 1502
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Personal name Shruti, Sonal
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9 (RLIN) 1503
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Personal name Kapanidou, Maria
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9 (RLIN) 1504
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Personal name Cheng, Xu
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Personal name Acierno, James
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Personal name Rademaker, Jesse
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9 (RLIN) 1507
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Personal name Rasika, S
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Personal name Quinton, Richard
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9 (RLIN) 1509
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Personal name Niedziela, Marek
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Personal name L'Allemand, Dagmar
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Personal name Pignatelli, Duarte
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Personal name Dirlewander, Mirjam
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9 (RLIN) 1513
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Personal name Lang-Muritano, Mariarosaria
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9 (RLIN) 1514
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Personal name Kempf, Patrick
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9 (RLIN) 1515
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Personal name Catteau-Jonard, Sophie
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9 (RLIN) 1516
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Personal name Niederländer, Nicolas J.
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9 (RLIN) 1517
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Personal name Ciofi, Philippe
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Personal name Tena-Sempere, Manuel
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Personal name Garthwaite, John
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9 (RLIN) 1520
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Personal name Storme, Laurent
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Personal name Avan, Paul
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Personal name Hrabovszky, Erik
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9 (RLIN) 1523
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Personal name Carleton, Alan
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9 (RLIN) 1524
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Personal name Santoni, Federico
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Personal name Giacobini, Paolo
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Personal name Pitteloud, Nelly
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Personal name Prevot, Vincent
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Note Sci Transl Med
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Uniform Resource Identifier <a href="http://dx.doi.org/10.1126/scitranslmed.abh2369">http://dx.doi.org/10.1126/scitranslmed.abh2369</a>
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