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Increasing the number of diagnostic mutations in malignant hyperthermia

Levano, Soledad and Vukcevic, Mirko and Singer, Martine and Matter, Anja and Treves, Susan and Urwyler, Albert and Girard, Thierry. (2009) Increasing the number of diagnostic mutations in malignant hyperthermia. Human Mutation, 30 (4). pp. 590-598.

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Official URL: http://edoc.unibas.ch/dok/A6003860

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Abstract

Malignant hyperthermia (MH) is an autosomal dominant disorder characterized by abnormal calcium homeostasis in skeletal muscle in response to triggering agents. Today, genetic investigations on ryanodine receptor type 1 (RYR1) gene and alpha1 subunit of the dihydropyridine receptor (DHPR) (CACNA1S) gene have improved the procedures associated with MH diagnosis. In approximately 50% of MH cases a causative RYR1 mutation was found. Molecular genetic testing based on RYR1 mutations for MH diagnosis is challenging, because the causative mutations, most of which are private, are distributed throughout the RYR1 gene. A more comprehensive genetic testing procedure is needed. Therefore, we aim to expand the genetic information related to MH and to evaluate the effect of mutations on the MH phenotype. Performing an in-depth mutation screening of the RYR1 transcript sequence in 36 unrelated MH susceptible (MHS) patients, we identified 17 novel, five rare, and eight non-disease-causing variants in 23 patients. The 13 remaining MHS patients presented no known variants, neither in RYR1 nor in the CACNA1S binding regions to RYR1. The 17 novel variants were found to affect highly conserved amino acids and were absent in 100 controls. Excellent genotype-phenotype correlations were found by investigating 21 MHS families-a total of 186 individuals. Epstein-Barr virus (EBV) lymphoblastoid cells carrying four of these novel mutations showed abnormal calcium homeostasis. The results of this study contribute to the establishment of a robust genetic testing procedure for MH diagnosis.
Faculties and Departments:03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Anästhesiologie > Anästhesie und Intensivmedizin (Urwyler)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Anästhesiologie > Anästhesie und Intensivmedizin (Urwyler)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Perioperative Patient Safety (Girard/Treves)
UniBasel Contributors:Urwyler, Albert and Girard, Thierry
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Wiley
ISSN:1059-7794
e-ISSN:1098-1004
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:31 May 2017 09:22
Deposited On:01 Mar 2013 11:13

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