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1.
Dis Model Mech ; 16(6)2023 06 01.
Article in English | MEDLINE | ID: mdl-37139703

ABSTRACT

Hypokalemic periodic paralysis (HypoPP) is a rare genetic disease associated with mutations in CACNA1S or SCN4A encoding the voltage-gated Ca2+ channel Cav1.1 or the voltage-gated Na+ channel Nav1.4, respectively. Most HypoPP-associated missense changes occur at the arginine residues within the voltage-sensing domain (VSD) of these channels. It is established that such mutations destroy the hydrophobic seal that separates external fluid and the internal cytosolic crevices, resulting in the generation of aberrant leak currents called gating pore currents. Presently, the gating pore currents are thought to underlie HypoPP. Here, based on HEK293T cells and by using the Sleeping Beauty transposon system, we generated HypoPP-model cell lines that co-express the mouse inward-rectifier K+ channel (mKir2.1) and HypoPP2-associated Nav1.4 channel. Whole-cell patch-clamp measurements confirmed that mKir2.1 successfully hyperpolarizes the membrane potential to levels comparable to those of myofibers, and that some Nav1.4 variants induce notable proton-based gating pore currents. Importantly, we succeeded in fluorometrically measuring the gating pore currents in these variants by using a ratiometric pH indicator. Our optical method provides a potential in vitro platform for high-throughput drug screening, not only for HypoPP but also for other channelopathies caused by VSD mutations.


Subject(s)
Hypokalemic Periodic Paralysis , Mice , Humans , Animals , Hypokalemic Periodic Paralysis/genetics , Hypokalemic Periodic Paralysis/metabolism , HEK293 Cells , Mutation/genetics , Ion Channel Gating , Cytosol/metabolism , NAV1.4 Voltage-Gated Sodium Channel/genetics , NAV1.4 Voltage-Gated Sodium Channel/metabolism
2.
Brain Dev ; 43(9): 952-957, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34092402

ABSTRACT

BACKGROUND: Familial hemiplegic migraine (FHM) is an inherited autosomal dominant disorder characterized by migraine with reversible hemiplegia. FHM1 is caused by variants in CACNA1A, encoding a P/Q type neuronal voltage-gated calcium channel α subunit, which is also associated with episodic ataxia type 2 (EA2). FHM2 is associated with ATP1A2, which codes for an Na+/K+-ATPase isoform 2 subunit. CASE PRESENTATION: We identified an FHM2 family, the mother and her daughter, with a novel variant in ATP1A2, p.Gly377Asp, located in a well-conserved P-type ATPase motif. Additionally, the mother harbored deletion in the CACNA1A, associated with EA2, but her daughter did not. The mother presented migraine with typical aura without motor deficit, whereas her daughter had migraine accompanied by recurrent motor deficit and altered consciousness. The additional CACNA1A deletion in the mother might serve as a modifier. CONCLUSION: Our report emphasizes the importance of genetic analysis to diagnose neurological ion channel/transporter diseases.


Subject(s)
Calcium Channels/genetics , Sodium-Potassium-Exchanging ATPase/genetics , Amino Acid Motifs , Female , Genetic Testing , Humans , Middle Aged , Migraine with Aura/diagnosis , Migraine with Aura/genetics , P-type ATPases/chemistry , Pedigree , Sodium-Potassium-Exchanging ATPase/chemistry
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