VP.04 Ryanodine receptor - related disorders

Abstract

The ryanodine receptors (RyR1) is the main sarcoplasmic reticulum Ca²⁺ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca²⁺-dependent muscle contraction. <i>RYR1</i> is expressed predominantly in fast and slow-twitch skeletal muscle and also in the esophagus and in cerebellar Purkinje cells in the brain. <i>RYR2</i> is the predominant isoform in cardiac muscle and brain. Its expression in the brain, brain stem, and spinal cord is widespread, but it is absent from the pituitary. <i>RYR3</i> is differentially expressed in the brain. Abnormal RyR1 activity compromises normal muscle function. RYR1-associated myopathies have been described as rare, histopathologically and clinically heterogeneous, and slowly progressive neuromuscular disorders. <i>RYR1</i> variants can lead to dysfunctional RyR1-mediated calcium release, malignant hyperthermia susceptibility, elevated oxidative stress, deleterious post-translational modifications, and decreased RyR1 expression. <i>RYR1</i> mutations cause disorders such as malignant hyperthermia, central core disease, congenital fibre type disproportion and centronuclear myopathy. However, <i>RYR1</i> is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe several <i>RYR</i> mutations and correlate them to the diseases. We also validated large deletion in ryanodine receptor 1 (<i>RYR1</i>) using droplet digital PCR.