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Malignant hyperthermia manifests as a rapid and sustained rise in temperature in response to pharmacological triggering agents, e.g. inhalational anesthetics and the muscle relaxant suxamethonium. Other clinical signs include an increase in end-tidal CO2, increased O2 consumption, as well as tachycardia, and if untreated a malignant hyperthermia episode can result in death. The metabolic changes are caused by dysregulation of skeletal muscle Ca2+ homeostasis, resulting from a defective ryanodine receptor Ca2+ channel, which resides in the sarcoplasmic reticulum and controls the flux of Ca2+ ions from intracellular stores to the cytoplasm. Most genetic variants associated with susceptibility to malignant hyperthermia occur in the RYR1 gene encoding the ryanodine receptor type 1. While malignant hyperthermia susceptibility can be diagnosed by in vitro contracture testing of skeletal muscle biopsy tissue, it is advantageous to use DNA testing. Currently only 35 of over 400 potential variants in RYR1 have been classed as functionally causative of malignant hyperthermia and thus can be used for DNA diagnostic tests. Here we describe functional analysis of 2 RYR1 variants (c. 7042_7044delCAG, p.ΔGlu2348 and c.641C>T, p.Thr214Met) that occur in the same malignant hyperthermia susceptible family. The p.Glu2348 deletion, causes hypersensitivity to ryanodine receptor agonists using in vitro analysis of cloned human RYR1 cDNA expressed in HEK293T cells, while the Thr214Met substitution, does not appear to significantly alter sensitivity to agonist in the same system. We suggest that the c. 7042_7044delCAG, p.ΔGlu2348 RYR1 variant could be added to the list of diagnostic mutations for susceptibility to malignant hyperthermia.

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IntroductionAsthma is a serious health problem with increased prevalence and incidence over recent decades in both children and adults. Identification of study subjects likely to have asthma is a key step in asthma investigations. Epidemiologic investigations have utilized questionnaires to determine asthma prevalence. [1][2][3][4][5][6] Currently there is no universally accepted standard definition of asthma for case identification in adult studies of asthma. It is essential to develop predictive models to identify asthma among adult populations. Dr. Deng and Ms Gebretsadik contributed to conception of the study, analysis and interpretation of the data and preparation of the manuscript. Drs Jin, Gao, Bai and Wen contributed data generation and critical review of the manuscript. Drs. Bai, Jin and Christman were involved in the methacholine challenge testing and interpretation, and critically reviewed the manuscript. Dr. Dupont, Mr. Plummer and Mr. Stephens contributed to analysis and interpretation of the data, development of the web-based interface, and preparation of the manuscript. Dr. Shu contributed to the generation of the data and critical review of the manuscript. Dr. Hartert contributed to the conception and design and all aspects of manuscript preparation, and is the principal investigator of the grant that supports this project.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptAnn Allergy Asthma Immunol. Author manuscript; available in PMC 2011 September 1. Methacholine challenge testing (MCT) and/or test of reversibility to short-acting beta-agonists are objective measurements used to assess bronchial hyperresponsiveness. However, there are practical limitations to performing this testing since it is costly, labor-intensive and timeconsuming, and there can be variability in results secondary to environmental and treatment factors. 14 Because of the expense, difficulty associated with this physiological testing, and questions regarding whether MCT should even represent a gold standard, questionnaires remain the principal instrument used to identify asthma in large population based epidemiologic studies.While most previous published studies have focused on the association of individual asthma related variables with the occurrence of asthma in adults, Pekkanen and colleagues have suggested that the sum of positive answers to asthma symptom questions as a continuous score is better than individual symptoms for studying the etiology of asthma. 15 The objective of the present study was to develop a scoring system to serve as an effic...

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