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

Abstract

BACKGROUND:

Altered 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.

METHODS:

This 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.

RESULTS:

Caffeine-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.

CONCLUSION:

The 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.

• Authors: 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, Sheila Muldoon
• Journal: Anesthesiology (Anesthesiology) Vol. 97 Issue 5 Pg. 1052-8 (Nov 2002) ISSN: 0003-3022 [Print] United States
• PMID: 12411786 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cresols
• Ryanodine Receptor Calcium Release Channel
• chlorocresol
• Caffeine
• Calcium
• Halothane

Topics

• Adolescent
• Adult
• B-Lymphocytes (metabolism)
• Caffeine
• Calcium (metabolism)
• Child
• Cresols
• Disease Susceptibility
• Halothane
• Humans
• Malignant Hyperthermia (diagnosis, genetics, metabolism)
• Middle Aged
• Muscle Contraction (drug effects)
• Mutation
• Ryanodine Receptor Calcium Release Channel (genetics)