De novovariants ofNALCNdifferentially impact both the phenotypic spectrum of patients and the biophysical properties of the NALCN current
Abstract
The Na+leak channel NALCN regulates the resting membrane potential and consequently cell excitability of several cell types, including neurons. Studies of animal models demonstrated that NALCN is involved in fundamental physiological functions such as respiratory rhythm, circadian rhythm, sleep, locomotor behavior and pain perception. Pathogenic variants ofNALCNhave been associated with ultra-rare developmental disorders characterized by a wide range of symptoms with variable severity. We and others previously showed that pathogenic variants ofNALCNcan be categorized in 2 groups. The first group corresponds to inherited biallelic loss-of-function variants with patients suffering from the IHPRF1 syndrome (OMIM #615419). The second one corresponds tode novogain-of-function variants that cause the CLIFAHDD syndrome (OMIM #616266). In this study, we provide a standardized phenotypic description of a large group of 35 individuals withde novopathogenic variants ofNALCN. In addition, we performed functional studies of several of these variants using the patch clamp technique in a recombinant system. We highlight a large heterogeneity in terms of both expressed symptoms and their severity. By contrast with previous reports only showing a pure gain-of-function effect ofde novopathogenic variants, we found thatde novovariants ofNALCNdifferentially impact the biophysical properties of the NALCN current and likely influence cell excitability. To conclude,de novovariants ofNALCNdifferentially impact the biophysical properties of the NALCN current. We hypothesize that this may at least partly explain the phenotypic diversity observed in patients.
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