• Anesthesiology · Nov 2002

    Patients with malignant hyperthermia demonstrate an altered calcium control mechanism in B lymphocytes.

    • Yoshitatsu Sei, Barbara W Brandom, Saiid Bina, Eiji Hosoi, Kathleen L Gallagher, Hadley W Wyre, Paul A Pudimat, Steve J Holman, David J Venzon, John W Daly, and Sheila Muldoon.
    • Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799, USA. ysei@usuhs.mil
    • Anesthesiology. 2002 Nov 1;97(5):1052-8.

    BackgroundAltered Ca2+ homeostasis in skeletal muscle is a key molecular event triggering malignant hyperthermia (MH) in malignant hyperthermia-susceptible (MHS) individuals. Genetic studies have shown that mutations in the type 1 ryanodine receptor (RYR1) are associated with MH susceptibility. Because human B lymphocytes express the RYR1, it is hypothesized that Ca2+ homeostasis in B lymphocytes is altered in MHS individuals.MethodsThis study investigated the Ca2+ response of B cells to caffeine and 4-chloro-m-cresol in 13 MHS and 21 MH-negative (MHN) individuals who had been diagnosed by caffeine halothane contracture test (CHCT) and 18 healthy volunteers. Changes in [Ca2+]i in B cells were measured directly in fluo-3 loaded cells using a dual-color flow cytometric technique. Further, B cell phenotype was correlated with CHCT results in a family with the Val2168Met (G6502A) mutation.ResultsCaffeine-induced (50 mm) increases in [Ca2+]i in B cells were significantly greater in MHS than in MHN (P = 0.0004), control (P = 0.0001) or non-MHS (MHN and control) individuals (P < 0.0001). The 4-chloro-m-cresol-induced (400 microm) increases in [Ca2+]i were also significantly different between MHS and controls (P = 0.003) or between MHS and non-MHS (MHN and control) individuals (P = 0.0078). A study of a family with the Val2168Met mutation demonstrated expression of the RYR1 mRNA mutant in B cells from the family members with MHS phenotype and a clear segregation of genotype with B-cell phenotype.ConclusionThe Ca2+ responses to caffeine or 4-chloro-m-cresol in B lymphocytes showed significant differences between MHS and MHN (or control) individuals. Although the molecular mechanisms of these alterations are currently undetermined, the results suggest that the enhanced Ca2+ responses are associated with mutations in the RYR1 gene in some MHS individuals.

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