Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Sci Rep ; 9(1): 11791, 2019 08 13.
Article in English | MEDLINE | ID: mdl-31409833

ABSTRACT

The excitability of neurons is tightly dependent on their ion channel repertoire. Among these channels, the leak sodium channel NALCN plays a crucial role in the maintenance of the resting membrane potential. Importantly, NALCN mutations lead to complex neurodevelopmental syndromes, including infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) and congenital contractures of limbs and face, hypotonia and developmental delay (CLIFAHDD), which are recessively and dominantly inherited, respectively. Unfortunately, the biophysical properties of NALCN are still largely unknown to date, as well as the functional consequences of both IHPRF and CLIFAHDD mutations on NALCN current. Here we have set-up the heterologous expression of NALCN in the neuronal cell line NG108-15 to investigate the electrophysiological properties of NALCN carrying representative IHPRF and CLIFAHDD mutations. Several original properties of the wild-type (wt) NALCN current were retrieved: mainly carried by external Na+, blocked by Gd3+, insensitive to TTX and potentiated by low external Ca2+ concentration. However, we found that this current displays a time-dependent inactivation in the -80/-40 mV range of membrane potential, and a non linear current-voltage relationship indicative of voltage sensitivity. Importantly, no detectable current was recorded with the IHPRF missense mutation p.Trp1287Leu (W1287L), while the CLIFAHDD mutants, p.Leu509Ser (L509S) and p.Tyr578Ser (Y578S), showed higher current densities and slower inactivation, compared to wt NALCN current. This study reveals that heterologous expression of NALCN channel can be achieved in the neuronal cell line NG108-15 to study the electrophysiological properties of wt and mutants. From our results, we conclude that IHPRF and CLIFAHDD missense mutations are loss- and gain-of-function variants, respectively.


Subject(s)
Channelopathies/genetics , Intellectual Disability/genetics , Ion Channels/genetics , Membrane Proteins/genetics , Muscle Hypotonia/genetics , Channelopathies/pathology , Facies , Humans , Intellectual Disability/pathology , Loss of Function Mutation/genetics , Membrane Potentials/genetics , Muscle Hypotonia/pathology , Mutation, Missense/genetics , Neurons/metabolism , Neurons/pathology , Psychomotor Disorders/genetics , Psychomotor Disorders/pathology , Sodium/metabolism , Sodium Channels/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...