Additional <i>de novo</i> missense genetic variants in <i><scp>NALCN</scp></i> associated with <scp>CLIFAHDD</scp> syndrome

Vivero, Matthew P.; Cho, M. T.; Begtrup, Amber; Wentzensen, Ingrid M.; Walsh, Laurence E.; Payne, Katelyn; Zárate, Yuri A.; Bosanko, Katherine A.; Schaefer, Gerald; DeBrosse, Suzanne D.; Pollack, Lynda; Mason, Kati J.; Retterer, Kyle; DeWard, Stephanie J.; Juusola, Jane; Chung, Wendy K.

doi:10.1111/cge.12899

Cited by 11 publications

(11 citation statements)

References 3 publications

(4 reference statements)

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“…In the last few years, both recessive and dominant human diseases characterized by a range of neurological symptoms including hypotonia, intellectual disability, and seizures, have been shown to be caused by mutations in either NALCN or UNC80 (Al-Sayed et al 2013;Köroglu et al 2013;Aoyagi et al 2015;Chong et al 2015;Bend et al 2016;Fukai et al 2016;Gal et al 2016;Karakaya et al 2016;Lozic et al 2016;Perez et al 2016;Shamseldin et al 2016;Stray-Pedersen et al 2016;Valkanas et al 2016;Wang et al 2016;Vivero et al 2017). Notably, dominant disease-causing mutations in the NALCN channel were modeled in worms and resemble either dominant activated or loss-of-function NCA mutants such as the ones we used in this study (Aoyagi et al 2015;Bend et al 2016).…”

Section: Discussionmentioning

confidence: 99%

The NCA-1 and NCA-2 Ion Channels Function Downstream of Gq and Rho To Regulate Locomotion in Caenorhabditis elegans

et al. 2017

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The heterotrimeric G protein G positively regulates neuronal activity and synaptic transmission. Previously, the Rho guanine nucleotide exchange factor Trio was identified as a direct effector of G that acts in parallel to the canonical G effector phospholipase C. Here, we examine how Trio and Rho act to stimulate neuronal activity downstream of G in the nematode Through two forward genetic screens, we identify the cation channels NCA-1 and NCA-2, orthologs of mammalian NALCN, as downstream targets of the G-Rho pathway. By performing genetic epistasis analysis using dominant activating mutations and recessive loss-of-function mutations in the members of this pathway, we show that NCA-1 and NCA-2 act downstream of G in a linear pathway. Through cell-specific rescue experiments, we show that function of these channels in head acetylcholine neurons is sufficient for normal locomotion in Our results suggest that NCA-1 and NCA-2 are physiologically relevant targets of neuronal G-Rho signaling in .

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Section: Discussionmentioning

confidence: 99%

The NCA-1 and NCA-2 Ion Channels Function Downstream of Gq and Rho To Regulate Locomotion in Caenorhabditis elegans

et al. 2017

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“…The structure of NALCN allowed us to locate all of the reported missense mutations identified in the NALCN subunit that cause diseases in human and model organisms (Fig. 1e, f) 7,9,10,17,[20][21][22][23][24][25][26][27] . The structure presented here is overall similar to the recently published structure of human NALCN-FAM155A complex (EMD-22203 and PDB ID: 6XIW) 18 ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Structure of voltage-modulated sodium-selective NALCN-FAM155A channel complex

Chen

2020

Nat Commun

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Resting membrane potential determines the excitability of the cell and is essential for the cellular electrical activities. The NALCN channel mediates sodium leak currents, which positively adjust resting membrane potential towards depolarization. The NALCN channel is involved in several neurological processes and has been implicated in a spectrum of neurodevelopmental diseases. Here, we report the cryo-EM structure of rat NALCN and mouse FAM155A complex to 2.7 Å resolution. The structure reveals detailed interactions between NALCN and the extracellular cysteine-rich domain of FAM155A. We find that the non-canonical architecture of NALCN selectivity filter dictates its sodium selectivity and calcium block, and that the asymmetric arrangement of two functional voltage sensors confers the modulation by membrane potential. Moreover, mutations associated with human diseases map to the domain-domain interfaces or the pore domain of NALCN, intuitively suggesting their pathological mechanisms.

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“…The structure of NALCN allowed us to locate all of the reported missense mutations identified in human diseases and model animals ( Fig. 1e, f) (Al-Sayed et al, 2013;Aoyagi et al, 2015;Campbell et al, 2018;Chong et al, 2015;Fukai et al, 2016;Funato et al, 2016;Karakaya et al, 2016;Lozic et al, 2016;Sivaraman et al, 2016;Vivero et al, 2017;Wang et al, 2016;Yeh et al, 2008).…”

Section: Structure Of the Nalcn-fam155a Core Complexmentioning

confidence: 99%

Structure of voltage-modulated sodium-selective NALCN-FAM155A channel complex

Chen

2020

Preprint

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Resting membrane potential determines the excitability of the cell and is essential for the cellular electrical activities. NALCN channel mediates sodium leak currents, which positively tune the resting membrane potential towards depolarization. NALCN channel is involved in many important neurological processes and is implicated in a spectrum of neurodevelopmental diseases. Despite its functional importance, the mechanisms of ion permeation and voltage-modulation for NALCN channel remain elusive. Here, we report the cryo-EM structure of rat NALCN and mouse FAM155A complex to 2.7 Å resolution. The structure reveals detailed interactions between NALCN and extracellular cysteine-rich domain of FAM155A. The non-canonical architecture of NALCN selectivity filter dictates its sodium selectivity and calcium block. The asymmetric arrangement of two functional voltage-sensors confers the modulation by membrane potential. Moreover, mutations found in human diseases were mapped to the domain-domain interfaces or the pore domain of NALCN, intuitively suggesting their pathological mechanisms.

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Additional de novo missense genetic variants in NALCN associated with CLIFAHDD syndrome

Cited by 11 publications

References 3 publications

The NCA-1 and NCA-2 Ion Channels Function Downstream of Gq and Rho To Regulate Locomotion in Caenorhabditis elegans

The NCA-1 and NCA-2 Ion Channels Function Downstream of Gq and Rho To Regulate Locomotion in Caenorhabditis elegans

Structure of voltage-modulated sodium-selective NALCN-FAM155A channel complex

Structure of voltage-modulated sodium-selective NALCN-FAM155A channel complex

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