Functional Characterization of Disease-Causing Mutations in the Sodium Leak Channel NALCN

The Na+ leak channel (NALCN) is highly expressed in the brain, where it mediates a persistent current that contributes to resting membrane potential (RMP) of neurons. This regulates neuronal excitability underlying processes, such as locomotion and circadian rhythm. Recently, we have shown, co-expression UNC80, UNC79 FAM155A required form functional NALCN complex heterologous systems. To date, over 60 pathogenic mutations been reported for causing severe developmental delay, congenital contractures limbs, hypotonia respiratory problems. Here, functionally characterize all known disease-causing using two-electrode voltage clamp Xenopus laevis oocytes, complemented by patch electrophysiology HEK293T cells. our surprise, found 31 missense or around pore, well DIII-IV linker, cause gain-of-function (GOF) phenotype, whereas nonsense UNC80 result complete loss function, despite robust cell surface expression truncated proteins. GOF phenotypes are characterized increased amplitudes out- inward currents, larger currents at negative potentials, depolarized RMP drastically altered kinetic properties opening. summary, performed first systematic characterization patient provide comprehensive overview their impacts. represents step towards mechanistic understanding channelopathies provides important insight into molecular function this essential channel.