RESUMEN
Malignant hyperthermia is a pharmacogenetic disorder associated with mutations in Ca(2+) regulatory proteins. It manifests as a hypermetabolic crisis triggered by commonly used anesthetics. Malignant hyperthermia susceptibility is a dominantly inherited predisposition to malignant hyperthermia that can be diagnosed by using caffeine/halothane contracture tests. In a multigenerational North American family with a severe form of malignant hyperthermia that has caused four deaths, a novel RYR1 A2350T missense mutation was identified in all individuals testing positive for malignant hyperthermia susceptibility. The same A2350T mutation was identified in an Argentinean family with two known fatal MH reactions. Functional analysis in HEK-293 cells revealed an altered Ca(2+) dependence and increased caffeine sensitivity of the expressed mutant protein thus confirming the pathogenic potential of the RYR1 A2350T mutation.
Asunto(s)
Hipertermia Maligna/genética , Mutación Missense , Canal Liberador de Calcio Receptor de Rianodina/genética , Sustitución de Aminoácidos , Argentina , Salud de la Familia , Femenino , Ligamiento Genético , Genotipo , Humanos , Masculino , Linaje , Fenotipo , Ensayo de Unión Radioligante , Rianodina/metabolismo , Rianodina/farmacología , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Tritio , Estados UnidosRESUMEN
We have found the codon 200Lys mutation in 6 Chilean CJD families, including a family in the rural case cluster in Chillán. Thus, all 3 of the known clusters of CJD, in Slovakia, Libyan-born Israeli Jews, and Chile, are linked to the presence of the same mutation. The phenotypic features of the disease in these families are similar to those reported for other clustered or individual families elsewhere in the world. The heterogeneous genetic composition of the Chilean population interpreted in light of historical migration patterns suggests that the mutation may have entered Chile by Jewish emigration from Spain.