Akinesia and freezing caused by Na<sup>+</sup> leak‐current channel (NALCN) deficiency corrected by pharmacological inhibition of K<sup>+</sup> channels and gap junctions

Kasap, Merve; Bonnett, K.; Aamodt, Eric J.; Dwyer, Donard S.

doi:10.1002/cne.24119

Cited by 14 publications

(12 citation statements)

References 45 publications

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“…Using a C . elegans model mimicking IHPRF, it was recently suggested that NALCN deficiency may be corrected by pharmacological targeting of other channels 58 . Conversely, one may predict that partial inhibition of NALCN could present some benefits for CLIFAHDD patients.…”

Section: Discussionmentioning

confidence: 99%

Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties

Bouasse

Impheng

Servant

et al. 2019

Sci Rep

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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 Gd 3+ , insensitive to TTX and potentiated by low external Ca 2+ 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.

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Section: Discussionmentioning

confidence: 99%

Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties

Bouasse

Impheng

Servant

et al. 2019

Sci Rep

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“…Therefore, we used a χ 2 test to evaluate whether differences between the treatment groups and the controls were statistically significant. We have previously employed the same statistical approach for the analysis of spontaneous movement in other strains [23]. The χ 2 method does not generate standard deviations.…”

Section: Methodsmentioning

confidence: 99%

“…At various times after transfer, we observed the animals individually for 5 s and scored them as “spontaneously moving” if they traveled more than 2 head lengths (about half their body length) in either direction as described elsewhere [23]. All incubation steps and observations were performed at 25°C or room temperature, respectively.…”

Section: Methodsmentioning

confidence: 99%

Insulin Signaling Deficiency Produces Immobility in Caenorhabditis elegans That Models Diminished Motivation States in Man and Responds to Antidepressants

Dagenhardt¹,

Trinh²,

Sumner

et al. 2017

Complex Psychiatry

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Defects in insulin signaling have been reported in schizophrenia and major depressive disorder, which also share certain negative symptoms such as avolition, anhedonia, and apathy. These symptoms reflect diminished motivational states, which have been modeled in rodents as increased immobility in the forced swimming test. We have discovered that loss-of-function mutations in the insulin receptor (daf-2) and syntaxin (unc-64) genes in Caenorhabditis elegans, brief food deprivation, and exposure to DMSO produce immobility and avolition in non-dauer adults. The animals remain responsive to external stimuli; however, they fail to forage and will remain in place for >12 days or until they die. Their immobility can be prevented with drugs used to treat depression and schizophrenia and that reduce immobility in the forced swimming test. This includes amitriptyline, amoxapine, clozapine, and olanzapine, but not benzodiazepines and haloperidol. Recovery experiments confirm that immobility is induced and maintained by excessive signaling via serotonergic and muscarinic cholinergic pathways. The immobility response described here represents a potential protophenotype for avolition/anhedonia in man. This work may provide clues about why there is a significant increase in depression in patients with diabetes and suggest new therapeutic pathways for disorders featuring diminished motivation as a prominent symptom.

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“…Furthermore, the routine use of a homozygosity data mapping algorithm might be helpful for improving the diagnostic yields of next‐generation sequencing without requiring the addition of an SNP array analysis. Recent loss‐of‐function studies for Nalcn in model organisms have suggested that neurological symptoms can be alleviated by the voltage gated K+ channel inhibitor 4‐aminopyridine (Kasap, Bonnett, Aamodt, & Dwyer, ). A precise diagnosis of this condition could have potential therapeutic implications.…”

Section: Discussionmentioning

confidence: 99%

Biallelic mutations in NALCN: Expanding the genotypic and phenotypic spectra of IHPRF1

Tamura

Inaba

Uehara

et al. 2017

American J of Med Genetics Pt A

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Loss-of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi-allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi-allelic splice site mutations, that is c.1267-2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022_2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next-generation sequencing.

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Akinesia and freezing caused by Na⁺ leak‐current channel (NALCN) deficiency corrected by pharmacological inhibition of K⁺ channels and gap junctions

Cited by 14 publications

References 45 publications

Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties

Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties

Insulin Signaling Deficiency Produces Immobility in Caenorhabditis elegans That Models Diminished Motivation States in Man and Responds to Antidepressants

Biallelic mutations in NALCN: Expanding the genotypic and phenotypic spectra of IHPRF1

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Akinesia and freezing caused by Na+ leak‐current channel (NALCN) deficiency corrected by pharmacological inhibition of K+ channels and gap junctions

Cited by 14 publications

References 45 publications

Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties

Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties

Insulin Signaling Deficiency Produces Immobility in Caenorhabditis elegans That Models Diminished Motivation States in Man and Responds to Antidepressants

Biallelic mutations in NALCN: Expanding the genotypic and phenotypic spectra of IHPRF1

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Akinesia and freezing caused by Na⁺ leak‐current channel (NALCN) deficiency corrected by pharmacological inhibition of K⁺ channels and gap junctions