title: Multigenerational Brazilian family with malignant hyperthermia and a novel mutation in the RYR1 gene.
abstract: Malignant hyperthermia (MH) is a pharmacogenetic disease triggered in susceptible individuals by the administration of volatile halogenated anesthetics and/or succinylcholine, leading to the development of a hypermetabolic crisis, which is caused by abnormal release of Ca2+ from the sarcoplasmic reticulum, through the Ca2+ release channel ryanodine receptor 1 (RyR1). Mutations in the RYR1 gene are associated with MH in the majority of susceptible families. Genetic screening of a 5-generation Brazilian family with a history of MH-related deaths and a previous MH diagnosis by the caffeine halothane contracture test (CHCT) in some individuals was performed using restriction and sequencing analysis. A novel missense mutation, Gly4935Ser, was found in an important functional and conserved locus of this gene, the transmembrane region of RyR1. In this family, 2 MH-susceptible individuals previously diagnosed with CHCT carry this novel mutation and another 24 not previously diagnosed members also carry it. However, this same mutation was not found in another MH-susceptible individual whose CHCT was positive to the test with caffeine but not to the test with halothane. None of the 5 MH normal individuals of the family, previously diagnosed by CHCT, carry this mutation, nor do 100 controls from control Brazilian and USA populations. The Gly4932Ser variant is a candidate mutation for MH, based on its co-segregation with disease phenotype, absence among controls and its location within the protein.
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
authors.forename: A R
authors.initials: AR
authors.lastname: Matos
authors.forename: N
authors.initials: N
authors.lastname: Sambuughin
authors.forename: F D
authors.initials: FD
authors.lastname: Rumjanek
authors.forename: N D
authors.initials: ND
authors.lastname: Amoedo
authors.forename: L B P
authors.initials: LB
authors.lastname: Cunha
authors.forename: G
authors.initials: G
authors.lastname: Zapata-Sudo
authors.forename: R T
authors.initials: RT
authors.lastname: Sudo
mesh_terms: D001938:Brazil; D002110:Caffeine; D003286:Contracture; D005190:Family; D005260:Female; D005820:Genetic Testing; D006221:Halothane; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D006221:Halothane