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1.
Hum Mutat ; 30(4): E575-90, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19191333

RESUMEN

Mutations in the RYR1 gene are linked to malignant hyperthermia (MH), central core disease and multi-minicore disease. We screened by DHPLC the RYR1 gene in 24 subjects for mutations, and characterized functional alterations caused by some RYR1 variants. Three novel sequence variants and twenty novel polymorphisms were identified. Immortalized lymphoblastoid cell lines from patients with RYR1 variants and from controls were stimulated with 4-chloro-m-cresol (4-CmC) and the rate of extracellular acidification was recorded. We demonstrate that the increased acidification rate of lymphoblastoid cells in response to 4-CmC is mainly due to RYR1 activation. Cells expressing RYR1 variants in the N-terminal and in the central region of the protein (p.Arg530His, p.Arg2163Pro, p.Asn2342Ser, p.Glu2371Gly and p.Arg2454His) displayed higher activity compared with controls; this could account for the MH-susceptible phenotype. Cell lines harboring RYR1(Cys4664Arg) were significantly less activated by 4-CmC. This result indicates that the p.Cys4664Arg variant causes a leaky channel and depletion of intracellular stores. The functional changes detected corroborate the variants analyzed as disease-causing alterations and the acidification rate measurements as a means to monitor Ca(2+)-induced metabolic changes in cells harboring mutant RYR1 channels.


Asunto(s)
Linfocitos B/metabolismo , Mutación , Canal Liberador de Calcio Receptor de Rianodina/genética , Linfocitos B/citología , Linfocitos B/efectos de los fármacos , Línea Celular Transformada , Cromatografía Líquida de Alta Presión/métodos , Cresoles/farmacología , Análisis Mutacional de ADN , Espacio Extracelular/química , Espacio Extracelular/efectos de los fármacos , Salud de la Familia , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Variación Genética , Humanos , Concentración de Iones de Hidrógeno , Masculino , Hipertermia Maligna/sangre , Hipertermia Maligna/diagnóstico , Hipertermia Maligna/genética , Miopatías Estructurales Congénitas/sangre , Miopatías Estructurales Congénitas/diagnóstico , Miopatías Estructurales Congénitas/genética , Linaje , Polimorfismo Genético , Canal Liberador de Calcio Receptor de Rianodina/fisiología
2.
Clin Chem Lab Med ; 41(1): 20-2, 2003 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-12636044

RESUMEN

We identified four novel polymorphisms in the CACNA1S gene that encodes the alpha1-subunit of the dihydropyridine receptor. Mutations in this gene are associated with two genetic diseases: malignant hyperthermia and hypokalemic periodic paralysis. The nucleotide substitutions c2403T --> C and c5398T --> C did not result in amino acid replacement, the nucleotide substitution c4475C --> A caused the replacement of the Ala1492 with an Asp residue and an A insertion was identified in intron 36. By using methods based on digestion with restriction enzymes we calculated the frequencies of these novel polymorphisms, as well as heterozygosity, in normal subjects from southern Italy.


Asunto(s)
Canales de Calcio Tipo L/genética , Hipertermia Maligna/genética , Polimorfismo Genético/genética , Sustitución de Aminoácidos/genética , Cartilla de ADN , Exones , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Intrones , Datos de Secuencia Molecular , Mapeo Restrictivo
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