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Mutation screening in the ryanodine receptor 1 gene (RYR1) in patients susceptible to malignant hyperthermia who show definite IVCT results: identification of three novel mutations.
Acta Anaesthesiol Scand. 2002 Jul; 46(6):692-8.AA

Abstract

BACKGROUND

The ryanodine receptor of the skeletal muscle (RYR1) seems to be of outstanding importance in the pathogenesis of malignant hyperthermia (MH). It has been shown that point mutations in the RYR1 gene are strongly associated with the MH phenotype. A correctly determined phenotype is the basic prerequisite for adequate genetic MH screening. In this study we examined only those MH susceptible patients for the presence of potential RYR1 mutations who showed strong pathological muscle responses in the in vitro contracture test (IVCT).

METHODS

A total of 56 MHS index patients who complied with the following IVCT criteria were included in the molecular genetic investigation: Contracture forces > or =4 mN at a caffeine concentration of 2.0 mmol/l and > or =8 mN at a halothane concentration of 0.44 mmol/l. DNA sequences of exons 2, 6, 9, 11, 12, 14, 15, 17, 39, 40, 45, 46, 102 of the RYR1 gene were analysed by the direct sequencing technique. Furthermore, if an MH mutation was identified in an index patient, all relatives were screened for their family specific RYR1 defect.

RESULTS

In 39 index patients an RYR1 mutation was detected: Arg163Cys (n = 2), Asp166Asn (n = 1), Gly341Arg (n = 2), Arg401His (n = 2), Arg614Cys (n = 12), Asp2129Glu (n = 1),Vol2168Met (n = 1), Thr2206Met (n = 9), Ala2428Thr (n = 1), Gly2434Arg (n = 2), Arg2435His (n = 1), Arg2452Trp (n = 1), Arg2454His (n = 4). Three new RYR1 mutations were identified. We found a potential MH mutation in a further 130 relatives of the 39 index patients. Thirty-seven individuals were classified as MHS exclusively by molecular genetic techniques and did not have to undergo the IVCT.

CONCLUSIONS

The ascertained high rate of successful MH mutation screening (69.64%) is obviously associated with the more clearly defined MHS diagnosis in the IVCT. According to the EMHG guidelines for the molecular genetic detection of MH susceptibility, a positive MH disposition could be determined in numerous persons by a less invasive technique.

Authors+Show Affiliations

Department of Anaesthesiology and Intensive Care Medicine, University of Leipzig, Leipzig, Germany. ruef@medizin.uni-leipzig.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12059893

Citation

Rueffert, Henrik, et al. "Mutation Screening in the Ryanodine Receptor 1 Gene (RYR1) in Patients Susceptible to Malignant Hyperthermia Who Show Definite IVCT Results: Identification of Three Novel Mutations." Acta Anaesthesiologica Scandinavica, vol. 46, no. 6, 2002, pp. 692-8.
Rueffert H, Olthoff D, Deutrich C, et al. Mutation screening in the ryanodine receptor 1 gene (RYR1) in patients susceptible to malignant hyperthermia who show definite IVCT results: identification of three novel mutations. Acta Anaesthesiol Scand. 2002;46(6):692-8.
Rueffert, H., Olthoff, D., Deutrich, C., Meinecke, C. D., & Froster, U. G. (2002). Mutation screening in the ryanodine receptor 1 gene (RYR1) in patients susceptible to malignant hyperthermia who show definite IVCT results: identification of three novel mutations. Acta Anaesthesiologica Scandinavica, 46(6), 692-8.
Rueffert H, et al. Mutation Screening in the Ryanodine Receptor 1 Gene (RYR1) in Patients Susceptible to Malignant Hyperthermia Who Show Definite IVCT Results: Identification of Three Novel Mutations. Acta Anaesthesiol Scand. 2002;46(6):692-8. PubMed PMID: 12059893.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutation screening in the ryanodine receptor 1 gene (RYR1) in patients susceptible to malignant hyperthermia who show definite IVCT results: identification of three novel mutations. AU - Rueffert,Henrik, AU - Olthoff,D, AU - Deutrich,C, AU - Meinecke,C D, AU - Froster,U G, PY - 2002/6/13/pubmed PY - 2002/10/17/medline PY - 2002/6/13/entrez SP - 692 EP - 8 JF - Acta anaesthesiologica Scandinavica JO - Acta Anaesthesiol Scand VL - 46 IS - 6 N2 - BACKGROUND: The ryanodine receptor of the skeletal muscle (RYR1) seems to be of outstanding importance in the pathogenesis of malignant hyperthermia (MH). It has been shown that point mutations in the RYR1 gene are strongly associated with the MH phenotype. A correctly determined phenotype is the basic prerequisite for adequate genetic MH screening. In this study we examined only those MH susceptible patients for the presence of potential RYR1 mutations who showed strong pathological muscle responses in the in vitro contracture test (IVCT). METHODS: A total of 56 MHS index patients who complied with the following IVCT criteria were included in the molecular genetic investigation: Contracture forces > or =4 mN at a caffeine concentration of 2.0 mmol/l and > or =8 mN at a halothane concentration of 0.44 mmol/l. DNA sequences of exons 2, 6, 9, 11, 12, 14, 15, 17, 39, 40, 45, 46, 102 of the RYR1 gene were analysed by the direct sequencing technique. Furthermore, if an MH mutation was identified in an index patient, all relatives were screened for their family specific RYR1 defect. RESULTS: In 39 index patients an RYR1 mutation was detected: Arg163Cys (n = 2), Asp166Asn (n = 1), Gly341Arg (n = 2), Arg401His (n = 2), Arg614Cys (n = 12), Asp2129Glu (n = 1),Vol2168Met (n = 1), Thr2206Met (n = 9), Ala2428Thr (n = 1), Gly2434Arg (n = 2), Arg2435His (n = 1), Arg2452Trp (n = 1), Arg2454His (n = 4). Three new RYR1 mutations were identified. We found a potential MH mutation in a further 130 relatives of the 39 index patients. Thirty-seven individuals were classified as MHS exclusively by molecular genetic techniques and did not have to undergo the IVCT. CONCLUSIONS: The ascertained high rate of successful MH mutation screening (69.64%) is obviously associated with the more clearly defined MHS diagnosis in the IVCT. According to the EMHG guidelines for the molecular genetic detection of MH susceptibility, a positive MH disposition could be determined in numerous persons by a less invasive technique. SN - 0001-5172 UR - https://www.unboundmedicine.com/medline/citation/12059893/Mutation_screening_in_the_ryanodine_receptor_1_gene__RYR1__in_patients_susceptible_to_malignant_hyperthermia_who_show_definite_IVCT_results:_identification_of_three_novel_mutations_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0001-5172&date=2002&volume=46&issue=6&spage=692 DB - PRIME DP - Unbound Medicine ER -