The sodium leak channel NALCN is a highly conserved crucial player of cell excitability

Electrical activity of excitable cells, such as neurons and endocrine cells, involves a coordinated and tightly regulated action of a panel of specialized proteins including ion channels, transporters, exchangers, and receptors for hormones and neurotransmitters (Kandel, 2013; Hille, 2001). Any alteration in the function of one component of this “Excitosome” induces a pathological state that may be not only severe, but also lethal in human. The sodium (Na+)-leak channel NALCN was isolated in 1999 (Lee et al, 1999) and later studies revealed that it conducts a background sodium influx and critically regulates the electrical activity of neurons (reviewed in Cochet-Bissuel et al, 2014). Indeed, disruption of NALCN expression in different types of neurons from several species led to a 15mV hyperpolarization of the resting membrane potential and a decrease of their firing rate (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 is mainly expressed in brain, spinal cord, heart and endocrine glands but also in the uterus and intestine. As a whole, functional studies revealed that NALCN is a crucial player of cell excitability and is involved in several fundamental physiological processes such as respiratory rhythm, circadian rhythm, locomotor behavior, pain sensitivity, sleep, gastrointestinal motility, systemic osmoregulation and parturition (reviewed in Cochet-Bissuel et al, 2014).

NALCN is involved in rare and severe genetic diseases

Both recessive and dominant pathogenic variants of human NALCN and its Unc80 ancillary subunit (e.g. an important partner for NALCN function) were recently described in several clinical and genetic studies (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). Recessive pathogenic variants of NALCN and Unc80 are linked to a syndrome referred to as infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) type 1 (OMIM #615419; 39 patients from 24 families) and type 2 (OMIM #616801; 32 patients from 21 families), respectively. Dominant pathogenic variants of NALCN are responsible for a syndrome referred to as congenital contractures of limbs and face, hypotonia and developmental delay (CLIFAHDD; OMIM #616266, 38 patients with de novo mutations). It was recently demonstrated the gain- and loss-of-function effects of mutations causing the CLIFAHDD and IHPRF1 syndromes respectively (Bouasse et al, 2019). Both IHPRF and CLIFAHDD patients exhibit complex clinical traits of variable severity that may cause premature death in some cases. Interestingly, IHPRF and CLIFAHDD patients exhibit common symptoms such as hypotonia, facial dimorphisms, global developmental delay, constipation, and respiratory defects. In addition, patients with the CLIFAHDD syndrome exhibit distal arthrogryposis. Unfortunately, there is no available treatment for patients to date and it is necessary to develop novel therapeutics.

Written in 2020
*2020 NUMBER OF PATIENTS

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