Core C will provide genetically characterized tissues to each of the projects and Core D. In addition they will engage in genetic discovery using genome wide exomic sequencing to find new mutations in patients whose susceptibility is unrelated to RyRI and CaV1.1. The PI is the Director of the UK MH diagnostic center that investigates more than 150 patients for MH susceptibility each year (more than 6000 in total) using muscle biopsy and in vitro contracture tests (IVCT). From experience of the last two years we anticipate that at least 50 patients each year will be susceptible and that 30-40 of these will harbor mutations in the RYRI gene. DNA and/or frozen skeletal muscle of more than 1800 susceptible individuals is available to further the aims of the overall program. Specifically Core C will: 1. Collect blood and skeletal muscle samples from patients attending for diagnosis of MH susceptibility 2. Identify molecular genetic variants associated with MH susceptibility using the following strategy: a. Screen for common mutations in RYR1 - if negative then; b. Use next-generation sequencing technology to sequence the exons of RYR1 and CACNA1S - if no mutations identified then; c. Use whole genome exon sequencing to identify genetic variants in genes other than RYRI and CACNA1S. Details of novel variants will be provided to Core B who will generate cDNA constructs for expression in appropriate cell lines to be investigated by Projects 1, 2 and 3. 3. Supply primary myoblast cultures from genotyped MHS and MHN patients to Core B for distribution to Projects 1, 2 and 3. 4. Supply human MH biopsy samples of specified genotype to Project 2 (snap frozen) for analysis of RYR1 post-translational modification and to Core D (glutaraldehyde fixed) for ultrastructural analysis. When possible findings will be compared with changes in murine models with the same genotype 5. Maintain a database that correlates clinical MH and IVCT phenotype data with genotype data to inform the program projects.

Public Health Relevance

Core C will provide human tissue and identify new mutations associated with malignant hyperthermia to ensure that the mechanistic discoveries of the projects apply to the human condition. The work of Core C will also contribute to furthering the utility of genetic diagnosis of MH, thereby reducing the number of patients requiring muscle biopsy.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAR1-MLB)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
United States
Zip Code
Lavorato, Manuela; Iyer, V Ramesh; Dewight, Williams et al. (2017) Increased mitochondrial nanotunneling activity, induced by calcium imbalance, affects intermitochondrial matrix exchanges. Proc Natl Acad Sci U S A 114:E849-E858
Holland, Erika B; Goldstone, Jared V; Pessah, Isaac N et al. (2017) Ryanodine receptor and FK506 binding protein 1 in the Atlantic killifish (Fundulus heteroclitus): A phylogenetic and population-based comparison. Aquat Toxicol 192:105-115
Zhang, Rui; Pessah, Isaac N (2017) Divergent Mechanisms Leading to Signaling Dysfunction in Embryonic Muscle by Bisphenol A and Tetrabromobisphenol A. Mol Pharmacol 91:428-436
Perni, Stefano; Lavorato, Manuela; Beam, Kurt G (2017) De novo reconstitution reveals the proteins required for skeletal muscle voltage-induced Ca2+ release. Proc Natl Acad Sci U S A 114:13822-13827
Linsley, Jeremy W; Hsu, I-Uen; Groom, Linda et al. (2017) Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3. Proc Natl Acad Sci U S A 114:E228-E236
Lavorato, Manuela; Gupta, Pawan K; Hopkins, Philip M et al. (2016) Skeletal Muscle Microalterations in Patients Carrying Malignant Hyperthermia-Related Mutations of the e-c Coupling Machinery. Eur J Transl Myol 26:6105
Ronjat, Michel; Feng, Wei; Dardevet, Lucie et al. (2016) In cellulo phosphorylation induces pharmacological reprogramming of maurocalcin, a cell-penetrating venom peptide. Proc Natl Acad Sci U S A 113:E2460-8
Franzini-Armstrong, Clara (2016) Can the Arrangement of RyR2 in Cardiac Muscle Be Predicted? Biophys J 110:2563-5
Hopkins, Philip M; Fiszer, Dorota; Shaw, Marie-Anne et al. (2016) In Reply. Anesthesiology 124:511
Polster, Alexander; Nelson, Benjamin R; Olson, Eric N et al. (2016) Stac3 has a direct role in skeletal muscle-type excitation-contraction coupling that is disrupted by a myopathy-causing mutation. Proc Natl Acad Sci U S A 113:10986-91

Showing the most recent 10 out of 73 publications