CACNA1S – Hypokalemic Periodic Paralysis

Hypokalemic periodic paralysis (HypoPP; MONDO:0008223) is an autosomal dominant skeletal muscle channelopathy characterized by episodic flaccid weakness associated with hypokalemia. CACNA1S (HGNC:1397) encodes the skeletal muscle L-type voltage-dependent calcium channel α1S subunit (CaV1.1), a critical voltage sensor for excitation–contraction coupling.

Genetic evidence for CACNA1S-HypoPP is robust. Initial linkage and mutation screening in 33 independent kindreds identified missense mutations at Arg1239 in S4 of domain IV in 11 probands (p.Arg1239His/Gly/Cys) (PMID:8004673). Subsequent analysis of 16 additional Caucasian families confirmed two predominant mutations, Arg528His and Arg1239His, with no founder effect (n = 32 probands) (PMID:7847370). A four-generation Chinese family (19 affected of 43 members) segregated a novel Arg528Gly variant, establishing segregation in 19 relatives (PMID:15726306). Variant spectrum is dominated by S4 arginine substitutions (missense), consistent with gain-of-function gating pore effects.

Segregation analyses demonstrate complete co-segregation of pathogenic alleles with disease in multiple large pedigrees. Incomplete penetrance in female carriers (∼80 %) has been documented for Arg528His, but male penetrance is near 100 %, illustrating sex-modulated expressivity (PMID:7847370). Recurrent de novo events have been reported, reinforcing variant pathogenicity.

Functional studies corroborate the genetic data. Whole-cell recordings from HypoPP myotubes carrying R528H show a modest reduction in L-type current density and slowed activation kinetics, without altered inactivation, implicating an activation defect (PMID:9852570). The V876E mutation in S3 of domain III generates a proton-permeable gating pore current and increased Na⁺ leak under physiological conditions, directly linking variant to membrane depolarization and episodic paralysis (PMID:29114033).

No convincing conflicting evidence has been reported. Alternative phenotypes (malignant hyperthermia) map to distinct regions or involve RYR1, with minimal overlap at CACNA1S.

Key Take-home: CACNA1S missense mutations at voltage-sensor arginines cause autosomal dominant HypoPP via gating pore currents; genetic testing and variant confirmation enable accurate diagnosis, family counseling, and targeted management.

References

• Cell • 1994 • Dihydropyridine receptor mutations cause hypokalemic periodic paralysis PMID:8004673
• American journal of human genetics • 1995 • Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families PMID:7847370
• Neuromuscular disorders • 1997 • Genotype-phenotype correlations of DHP receptor alpha 1-subunit gene mutations causing hypokalemic periodic paralysis PMID:9132138
• Journal of molecular medicine (Berlin, Germany) • 2005 • Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family PMID:15726306
• 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

Evidence Based Scoring (AI generated)