El canal de fuga de sodio NALCN es un jugador crucial altamente conservado de la excitabilidad celular

La actividad eléctrica de las células excitables, como las neuronas y las células endocrinas, implica una acción coordinada y estrictamente regulada de un panel de proteínas especializadas que incluyen canales iónicos, transportadores, intercambiadores y receptores de hormonas y neurotransmisores (Kandel, 2013; Hille, 2001). Cualquier alteración en la función de un componente de este «Excitosoma» induce un estado patológico que puede ser no solo grave sino también letal en humanos. El sodio (Na +) - canal de fuga NALCN se aisló en 1999 (Lee et al, 1999) y estudios posteriores revelaron que conduce un influjo de sodio de fondo y regula críticamente la actividad eléctrica de las neuronas (revisado en Cochet-Bissuel et al, 2014). De hecho, la interrupción de la expresión de NALCN en diferentes tipos de neuronas de varias especies condujo a una hiperpolarización de 15mV del potencial de membrana en reposo y una disminución de su tasa de disparo (Lu et al, 2007, Lu et al, 2011; Xie et al, 2013 ; Gao et al, 2015; Flourakis et al, 2015; Lutas et al, 2016; Shi et al, 2016; Yeh et al, 2017; Ford et al, 2018). NALCN se expresa principalmente en el cerebro, la médula espinal, el corazón y las glándulas endocrinas, pero también en el útero y el intestino. En general, los estudios funcionales revelaron que NALCN es un jugador crucial de la excitabilidad celular y está involucrado en varios procesos fisiológicos fundamentales como el ritmo respiratorio, el ritmo circadiano, el comportamiento locomotor, la sensibilidad al dolor, el sueño, la motilidad gastrointestinal, la osmoregulación sistémica y el parto (revisado en Cochet-Bissuel et al, 2014).

NALCN está involucrado en enfermedades genéticas raras y graves

Las variantes patogénicas recesivas y dominantes de NALCN en humanos y su subunidad auxiliar Unc80 (por ejemplo, un socio importante para la función NALCN), se describieron recientemente en varios estudios clínicos y genéticos (Al-Sayed et al, 2013; Koroglu et al, 2013; Gal et al. , 2016; Takenouchi et al, 2017; Chong et al, 2015; Aoyagi et al, 2015; Wang et al, 2016; Fukai et al, 2016; Karakaya et al, 2016; Sivaraman et al, 2016; Bend et al, 2016 ; Lozic et al, 2016; Vivero et al, 2017; Perez et al, 2016; Shamseldin et al, 2016; Stray-Pedersen et al, 2016; Valkanas et al, 2016; Cherot et al, 2018; Angius et al, 2018 ; Obeid et al, 2018; Campbell et al, 2018; He et al, 2018; Bourque et al, 2018; Hong et al, 2018; Bramswig et al, 2018; Carneiro et al, 2018; Angius et al, 2019; Kuptanon et al, 2019). Las variantes patogénicas recesivas de NALCN y Unc80 están relacionadas con un síndrome denominado hipotonía infantil con retraso psicomotor y facies características (IHPRF) tipo 1 (OMIM # 615419; 39 pacientes de 24 familias) y tipo 2 (OMIM # 616801; 32 pacientes de 21 familias), respectivamente. Las variantes patogénicas dominantes de NALCN son responsables de un síndrome denominado contracturas congénitas de extremidades y cara, hipotonía y retraso del desarrollo (CLIFAHDD; OMIM # 616266, 38 pacientes con mutaciones de Novo). Recientemente se demostró los efectos de ganancia y pérdida de función de las mutaciones que causan los síndromes CLIFAHDD e IHPRF1 respectivamente (Bouasse et al, 2019). Tanto los pacientes con IHPRF como con CLIFAHDD exhiben rasgos clínicos complejos de gravedad variable que pueden causar la muerte prematura en algunos casos. Curiosamente, los pacientes con IHPRF y CLIFAHDD presentan síntomas comunes como hipotonía, dismorfismos faciales, retraso global del desarrollo, estreñimiento y defectos respiratorios. Además, los pacientes con el síndrome CLIFAHDD exhiben artrogriposis distal. Desafortunadamente, no hay un tratamiento disponible para los pacientes hasta la fecha y es necesario desarrollar nuevas terapias.

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