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 Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ 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 levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten 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 Ca2+ 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 the previous knowledge accumulated on DHPR.
Keywords
Male
Middle Aged
Muscle Cells/metabolism/pathology
Muscle
Skeletal/diagnostic imaging/metabolism/pathology
Mutation
Myotonia Congenita/diagnostic imaging/*genetics/*metabolism/pathology
Phenotype
Sequence Homology
Amino Acid
Young Adult
Centronuclear myopathy
Congenital myopathy
Core myopathy
Dhpr
Excitation-contraction coupling
Myotubular myopathy
Triad
Adolescent
Adult
Calcium/metabolism
Calcium Channels/*genetics/*metabolism
Cells
Cultured
Child
Cohort Studies
Family
Female
Humans