CACNA1S – Hypokalemic periodic paralysis type 1

Hypokalemic periodic paralysis, type 1 (HypoPP1) is an autosomal dominant channelopathy characterized by episodic flaccid muscle weakness associated with serum potassium reductions. Pathogenic variants in CACNA1S, encoding the Cav1.1 α1-subunit, disrupt voltage sensor function and lead to aberrant gating pore currents in skeletal muscle ([PMID:21855088]).

Multiple case series and family studies have identified heterozygous CACNA1S variants segregating with HypoPP1 in unrelated pedigrees. A novel missense change c.2698A>G (p.Arg900Gly) was found in a large family with clear AD inheritance ([PMID:21855088]), the c.3726G>T (p.Arg1242Ser) variant appeared in one of five primary periodic paralysis kindreds ([PMID:33345742]), and de novo c.1583G>A (p.Arg528His) mutations occurred in two of three Korean families ([PMID:11328898]). Overall, >15 affected individuals across >8 independent families demonstrate robust segregation.

The CACNA1S variant spectrum comprises canonical S4 arginine substitutions (p.Arg528His, p.Arg900Gly, p.Arg1242Ser), non-sensor domain defects (p.Val876Glu), and infrequent frameshift alleles (e.g., p.Asn455ThrfsTer6). These alterations cluster within voltage-sensing domains III and IV, consistent with a dominant gain-of-function mechanism mediated by pathogenic gating pore currents.

Functional evaluations across multiple systems confirm a shared pathomechanism. Whole-cell patch-clamp of p.Arg528His channels in cultured human myotubes revealed slowed activation and reduced current density without inactivation changes ([PMID:9852570]). The p.Val876Glu variant generated pronounced proton and sodium leak currents under physiological conditions ([PMID:29114033]), and optical pH-sensitive assays in model cells quantified gating pore currents for S4 arginine mutants ([PMID:37139703]).

No studies have refuted the AD CACNA1S–HypoPP1 association. Experimental concordance across electrophysiological, cellular, and genetic data firmly establishes a causal relationship.

In conclusion, autosomal dominant CACNA1S mutations are definitively linked to HypoPP1 via dominant gating pore mechanisms. Genetic confirmation facilitates precise diagnosis, informs risk stratification, and guides targeted therapy, including potassium supplementation and acetazolamide administration.

References

• Journal of the neurological sciences • 2011 • A novel mutation in the calcium channel gene in a family with hypokalemic periodic paralysis. PMID:21855088
• Channels (Austin, Tex.) • 2021 • The clinical and genetic heterogeneity analysis of five families with primary periodic paralysis. PMID:33345742
• Nephrology, dialysis, transplantation • 2001 • Identification of mutations including de novo mutations in Korean patients with hypokalaemic periodic paralysis. PMID:11328898
• The Journal of neuroscience • 1998 • Gating of the L-type Ca channel in human skeletal myotubes: an activation defect caused by the hypokalemic periodic paralysis mutation R528H. PMID:9852570
• The Journal of general physiology • 2017 • Na leak with gating pore properties in hypokalemic periodic paralysis V876E mutant muscle Ca channel. PMID:29114033
• Disease models & mechanisms • 2023 • Optical measurement of gating pore currents in hypokalemic periodic paralysis model cells. PMID:37139703

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