| 000 | 03955 am a22006013u 4500 | ||
|---|---|---|---|
| 042 | _adc | ||
| 100 | 1 | 0 |
_aChachlaki, Konstantina _eauthor _91494 |
| 700 | 1 | 0 |
_aMessina, Andrea _eauthor |
| 700 | 1 | 0 |
_aDelli, Virginia _eauthor _91496 |
| 700 | 1 | 0 |
_aLeysen, Valerie _eauthor |
| 700 | 1 | 0 |
_aMaurnyi, Csilla _eauthor _91498 |
| 700 | 1 | 0 |
_aHuber, Chieko _eauthor _91499 |
| 700 | 1 | 0 |
_aTernier, Gaëtan _eauthor _91500 |
| 700 | 1 | 0 |
_aSkrapits, Katalin _eauthor _91501 |
| 700 | 1 | 0 |
_aPapadakis, Georgios _eauthor _91502 |
| 700 | 1 | 0 |
_aShruti, Sonal _eauthor _91503 |
| 700 | 1 | 0 |
_aKapanidou, Maria _eauthor _91504 |
| 700 | 1 | 0 |
_aCheng, Xu _eauthor _91505 |
| 700 | 1 | 0 |
_aAcierno, James _eauthor |
| 700 | 1 | 0 |
_aRademaker, Jesse _eauthor _91507 |
| 700 | 1 | 0 |
_aRasika, S _eauthor |
| 700 | 1 | 0 |
_aQuinton, Richard _eauthor _91509 |
| 700 | 1 | 0 |
_aNiedziela, Marek _eauthor _91510 |
| 700 | 1 | 0 |
_aL'Allemand, Dagmar _eauthor _91511 |
| 700 | 1 | 0 |
_aPignatelli, Duarte _eauthor _91512 |
| 700 | 1 | 0 |
_aDirlewander, Mirjam _eauthor _91513 |
| 700 | 1 | 0 |
_aLang-Muritano, Mariarosaria _eauthor _91514 |
| 700 | 1 | 0 |
_aKempf, Patrick _eauthor _91515 |
| 700 | 1 | 0 |
_aCatteau-Jonard, Sophie _eauthor _91516 |
| 700 | 1 | 0 |
_aNiederländer, Nicolas J. _eauthor _91517 |
| 700 | 1 | 0 |
_aCiofi, Philippe _eauthor |
| 700 | 1 | 0 |
_aTena-Sempere, Manuel _eauthor |
| 700 | 1 | 0 |
_aGarthwaite, John _eauthor _91520 |
| 700 | 1 | 0 |
_aStorme, Laurent _eauthor _91521 |
| 700 | 1 | 0 |
_aAvan, Paul _eauthor _91522 |
| 700 | 1 | 0 |
_aHrabovszky, Erik _eauthor _91523 |
| 700 | 1 | 0 |
_aCarleton, Alan _eauthor _91524 |
| 700 | 1 | 0 |
_aSantoni, Federico _eauthor |
| 700 | 1 | 0 |
_aGiacobini, Paolo _eauthor |
| 700 | 1 | 0 |
_aPitteloud, Nelly _eauthor |
| 700 | 1 | 0 |
_aPrevot, Vincent _eauthor |
| 245 | 0 | 0 | _aNOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits: reversal with NO therapy in infantile mice |
| 260 | _c2022-10-05. | ||
| 500 | _a/pmc/articles/PMC7613826/ | ||
| 500 | _a/pubmed/36197968 | ||
| 520 | _aBACKGROUND: 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. | ||
| 540 | _a | ||
| 546 | _aen | ||
| 690 | _aArticle | ||
| 655 | 7 |
_aText _2local |
|
| 786 | 0 | _nSci Transl Med | |
| 856 | 4 | 1 |
_uhttp://dx.doi.org/10.1126/scitranslmed.abh2369 _zConnect to this object online. |
| 999 |
_c1967 _d1967 |
||