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In the present study, we generated large deletions of approximately 41.55\u2009kb in the <jats:italic>RMST<\/jats:italic> gene in human pluripotent stem cells using CRISPR\/Cas9 gene editing. To evaluate the impact of <jats:italic>RMST<\/jats:italic> deletion, these cells were differentiated into hypothalamic neurons that include 10\u201315% neurons that express gonadotrophin-releasing hormone (GnRH). We found that deletion in <jats:italic>RMST<\/jats:italic> did not impair the neurogenesis of GnRH neurons, however, the hypothalamic neurons were electro-physiologically hyperactive and had increased calcium influx activity compared to control. Transcriptomic and epigenetic analyses showed that <jats:italic>RMST<\/jats:italic> deletion caused altered expression of key genes involved in neuronal development, ion channels, synaptic signaling and cell adhesion. The in vitro generation of these <jats:italic>RMST<\/jats:italic>-deleted GnRH neurons provides an excellent cell-based model to dissect the molecular mechanism of <jats:italic>RMST<\/jats:italic> function in Kallmann syndrome and its role in hypothalamic neuronal development.<\/jats:p>","DOI":"10.1038\/s41420-024-02074-4","type":"journal-article","created":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T17:01:24Z","timestamp":1721408484000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Deletion in RMST lncRNA impairs hypothalamic neuronal development in a human stem cell-based model of Kallmann Syndrome"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3885-0556","authenticated-orcid":false,"given":"Gowher","family":"Ali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung Chul","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisar","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesal","family":"Habbab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghaneya","family":"Alkhadairi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleem","family":"Razzaq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosra","family":"Bejaoui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nady","family":"El Hajj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borbala","family":"Mifsud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongsoo","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence W.","family":"Stanton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,19]]},"reference":[{"key":"2074_CR1","doi-asserted-by":"publisher","first-page":"37","DOI":"10.12703\/r\/10-37","volume":"10","author":"DS Swee","year":"2021","unstructured":"Swee DS, Quinton R, Maggi R. 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