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A-1603
2004 |
| Comprehensive Screening of the RYR1 Gene for Malignant Hyperthermia Susceptibility |
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Nyamkhishig Sambuughin, Ph.D., Heather Holley, B.S., Barbara Brandom, M.D., Tom Nelson, Ph.D., Sheila Muldoon, M.D. Neurology Research, Barrow Neurological Institute, Phoenix, Arizona. |
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Malignant Hyperthermia (MH) is life-threatening hypermetabolic disorder that occurs following exposure to commonly used inhalational anesthetics. In the majority of cases, MH results from a defect in regulation of calcium release in skeletal muscle due to dominant mutations in the calcium channel of sarcoplasmic reticulum, ryanodine receptor (RYR1 at 19q13). Because of large size of the RYR1 gene, most genetic screening studies targeted only known mutational hot spots and as consequence mutations were identified in only about 25% of studied patients. The aim of this study was to develop an efficient method of finding most, if not all mutations in the RYR1 gene. We analyzed the entire coding region of the RYR1 gene using the WAVE nucleic acid fragment analysis system based on denaturing high-performance liquid chromatography (DHPLC) followed by DNA sequencing. The study was based on RT-PCR approach with use of total RNA extracted from muscles of individuals (N=30) diagnosed as MH Susceptible (MHS) by caffeine halothane contracture test (CHCT). Eight known mutations and eight novel amino-acid substitutions were found in the RYR1 gene. All new amino acid changes are likely candidate mutations for MHS because they cosegergate with disease, are absent among 50 healthy controls and are located at conserved residues within RYR1 proteins. Two novel candidate mutations were located outside of known mutational hot spots. Our preliminary data suggest that mutations in the RYR1 gene are distributed throughout the gene and the frequency of mutations can be increased from 25% to 63% with use of highly sensitive screening technique such as DHPLC. Funded by APSF and MHAUS grants. Anesthesiology 2004; 101: A1603 |