C57BL/6JCya-Cacna1s^em1flox/Cya

CACNA1S, encoding the alpha 1 S-subunit of the voltage-gated calcium channel, is mainly expressed in skeletal muscle cells. It is crucial for muscle function as it is involved in the process of excitatory-contractile coupling, which links muscle membrane depolarization to calcium release and subsequent muscle contraction [1,3,5].

Pathogenic variants of CACNA1S can lead to multiple disorders. For instance, they can cause hypokalemic periodic paralysis (HypoPP), where patients experience recurrent muscle weakness and hypokalemia [1,8]. In a case, a child with HypoPP had a novel c.497 C > A (p.Ala166Asp) variant of CACNA1S inherited from his father [1]. Mutations in this gene are also associated with malignant hyperthermia susceptibility, a life-threatening hypermetabolic state of skeletal muscle usually triggered by certain anesthetics [3,6]. Additionally, congenital myopathy can be caused by CACNA1S mutations, with phenotypes ranging from severe early-onset lethal forms to mild-moderate forms [2]. Some patients with CACNA1S-associated myopathy present with exercise-induced myalgia, muscle stiffness, fatigue, and eventually muscle weakness [4]. A rare c.2893G > C (p.E965Q) variant was identified in a Finnish family with such symptoms [4]. Moreover, a c.3724A > G (p.Arg1242Gly) mutation in CACNA1S was found in an autosomal-dominant family, where affected individuals had severe exertional myalgia, followed by flaccid weakness or rhabdomyolysis, and asymptomatic hyperCKemia during the interictal period [5]. Some patients with CACNA1S mutations also show dental anomalies, like molars with multiple supernumerary cusps, single-cusped premolars, and a reduction in root number, suggesting a role of calcium signaling in tooth development [7].

In conclusion, CACNA1S is essential for normal muscle function through its role in excitatory-contractile coupling. Research on CACNA1S-associated mutations has expanded our understanding of various muscle-related diseases such as HypoPP, malignant hyperthermia, congenital myopathy, and myalgic myopathies. The identification of specific mutations in CACNA1S provides insights into the genetic basis of these disorders, which may potentially contribute to early genetic diagnosis, genetic counseling, and proper treatment [1,2,3,4,5,7,8].