Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy

Abstract

Muscle contraction upon nerve stimulation relies on excitation-contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca 2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca 2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here we characterize a novel class of congenital myopathy at the morphological, molecular and functional level. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in 4 patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation in some samples, internal nuclei and areas of myofibrillar disorganization. Exome sequencing revealed 10 recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca 2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by previous knowledge accumulated on DHPR.

Novel SPEG mutations in congenital myopathies: Genotype–phenotype correlations

“…Centronuclear myopathies (CNMs) are a subtype characterized by increased central nuclei within myofibers, and often associated with disruption of excitation‐contraction coupling . Approximately 60–80% of CNMs are caused by dominant DNM2 mutations, dominant and recessive RYR1 and CACNA1S mutations, recessive BIN1 mutations, and X‐linked recessive MTM1 mutations . Recently, recessive SPEG mutations have been identified in 6 CNM patients and 1 patient with non‐CNM CM .…”

Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies

“…Ryanodine receptor type 3 may represent an additional example of an increasing number of genes encoding components of Ca 2+ release-activated channels, recently found to be involved in human myopathies, and also dihydropyridine receptor causing myopathy [21]. Association of mutations in these genes with muscle diseases further defines the expression pattern of RYR1 and RYR3 in human tissues as well as its subcellular localization in skeletal muscle, suggesting that RYR3 may play a role in skeletal muscle that is distinct from that of RYR1.…”

Abnormal Excitation-Contraction Coupling and Calcium Homeostasis in Myopathies and Cardiomyopathies

“…The voltage sensor and pore-forming subunit ␣1, encoded by CACNA1S in skeletal muscle and by CACNA1C in heart, contains four transmembrane domains (I-IV), and the cytoplasmic loop between domains II and III mediates the activation of the ryanodine receptor in skeletal muscle [16,17]. CACNA1S mutations have been associated with different disorders such as malignant hyperthermia (MH, OMIM #601887) [18], hypokalemic periodic paralysis (HOKPP, OMIM #170400) [19], and recently also with a new congenital myopathy entity [20], while CACNA1C mutations have been reported in Brugada syndrome (BrS, OMIM #611875) [21] and in Timothy syndrome (TS, OMIM #601005) [22].…”

“…Functional studies in the mouse model demonstrated that the loss of the pos- itive charge impacts on the gating properties of the channel by causing an anomalous voltage-dependent inward current [32]. CACNA1S mutations were also associated with an unusual congenital myopathy with both dominant and recessive disease inheritance [20]. All patients had a comparable clinical presentation of generalized muscle weakness at birth, and the muscle biopsies exhibited cores, central nuclei, dilated triads, as well as a particular alveolar aspect of the intermyofibrillar network.…”