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- Title
Deletion in RMST lncRNA impairs hypothalamic neuronal development in a human stem cell-based model of Kallmann Syndrome.
- Authors
Ali, Gowher; Shin, Kyung Chul; Ahmed, Nisar; Habbab, Wesal; Alkhadairi, Ghaneya; Razzaq, Aleem; Bejaoui, Yosra; El Hajj, Nady; Mifsud, Borbala; Park, Yongsoo; Stanton, Lawrence W.
- Abstract
Rhabdomyosarcoma 2-associated transcript (RMST) long non-coding RNA has previously been shown to cause Kallmann syndrome (KS), a rare genetic disorder characterized by congenital hypogonadotropic hypogonadism (CHH) and olfactory dysfunction. In the present study, we generated large deletions of approximately 41.55 kb in the RMST gene in human pluripotent stem cells using CRISPR/Cas9 gene editing. To evaluate the impact of RMST deletion, these cells were differentiated into hypothalamic neurons that include 10–15% neurons that express gonadotrophin-releasing hormone (GnRH). We found that deletion in RMST 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 RMST deletion caused altered expression of key genes involved in neuronal development, ion channels, synaptic signaling and cell adhesion. The in vitro generation of these RMST-deleted GnRH neurons provides an excellent cell-based model to dissect the molecular mechanism of RMST function in Kallmann syndrome and its role in hypothalamic neuronal development.
- Subjects
KALLMANN syndrome; ION channels; PLURIPOTENT stem cells; LINCRNA; HUMAN stem cells; CONGENITAL disorders
- Publication
Cell Death Discovery, 2024, Vol 10, Issue 1, p1
- ISSN
2058-7716
- Publication type
Article
- DOI
10.1038/s41420-024-02074-4