Identification of Genetic Mutations in Australian Malignant Hyperthermia Families Using Sequencing of Ryr1 Hotspots
| Autor: | D. Du Sart, M. Davis, Andrew R. Bjorksten, R. L. Gillies |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Pathology
medicine.medical_specialty DNA Mutational Analysis Critical Care and Intensive Care Medicine DNA sequencing Chromosome 19 medicine Homeostasis Humans Muscle Skeletal Gene DNA Primers RYR1 Muscle biopsy medicine.diagnostic_test Reverse Transcriptase Polymerase Chain Reaction business.industry Ryanodine receptor Australia Malignant hyperthermia Ryanodine Receptor Calcium Release Channel DNA medicine.disease Pedigree Anesthesiology and Pain Medicine Amino Acid Substitution Haplotypes Contracture medicine.symptom Malignant Hyperthermia business Chromosomes Human Pair 19 Muscle Contraction |
| Zdroj: | Anaesthesia and Intensive Care. 36:391-403 |
| ISSN: | 1448-0271 0310-057X |
| DOI: | 10.1177/0310057x0803600311 |
| Popis: | Advances in analysis of the RYR1 gene (which encodes the skeletal muscle ryanodine receptor) show that genetic examination is a useful adjunct to the in vitro contracture test in the diagnosis of malignant hyperthermia, as defects in RYR1 have been shown to be responsible for malignant hyperthermia susceptibility. DNA from 34 malignant hyperthermia susceptible individuals and four malignant hyperthermia equivocal subjects was examined using direct sequencing of ‘hotspots’ in the RYR1 gene to identify mutations associated with malignant hyperthermia. Seven different causative mutations (as defined by the European Malignant Hyperthermia Group) in nine malignant hyperthermia susceptible individuals were identified. In another six malignant hyperthermia susceptible individuals, five different published but as yet functionally uncharacterised mutations were identified. A further three as yet unpublished and functionally uncharacterised (novel) mutations were identified in three malignant hyperthermia susceptible samples. If the novel and previously published mutations prove to be functionally associated with calcium homeostasis, then this method of analysis achieved a mutation detection rate of 47%. Based on the number of relatives presenting to our unit in the study period, the muscle biopsy rate would have decreased by 25%. That we only identified a genetic defect in RYR1 in 47% of in vitro contracture test positive individuals suggests that there are other areas in RYR1 where pathogenic mutations may occur and that RYR1 may not be the sole gene associated with malignant hyperthermia. It may also reflect a less than 100% specificity of the in vitro contracture test. |
| Databáze: | OpenAIRE |
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