Phenotyping and Genotyping of the Ryanodine Receptor-Associated Genetic Diseases Using Peripheral Lymphocytes

Mutations in the genes encoding the ryanodine receptor, a Ca2+ release channel, cause autosomal-dominant diseases of skeletal and cardiac muscle such as malignant hyperthermia (MH), central core disease (CCD), catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular dysplasia Type 2 (ARVD2). Although some of these have congenital myopathies, these ryanodine receptor diseases are all pharmacogenetic. Difficulty in phenotyping and genotyping has significantly slowed the progress in clinical and basic research of these genetic diseases. Interestingly, skeletal muscle type (Type 1, RyR1) and cardiac muscle type (Type 2, RyR2) of the ryanodine receptors are expressed in peripheral B and T lymphocytes, respectively. RyR1-mediated Ca2+ response in B cells has been used to develop a non-invasive test to predict susceptibility to MH and CCD. Converging lines of evidence now suggest that RyR1-mediated calcium phenotype in B cells or Epstein-Barr virus-transformed B lymphoblasts reflect the RyR1-mediated phenotype in MHS / CCD muscle. Similarly, RyR2 expressed in T cells is available to study CPVT / FPVT and ARVD2. Therefore, a ryanodine receptor gene-based system that integrates information from cells, transcripts and proteins can be developed using peripheral lymphocytes to study and diagnose the ryanodine receptor diseases. Use of genes expressed in lymphocytes can be extended and applied to other genetic diseases based on functional genomics.