Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Más filtros

Bases de datos
Tipo de estudio
Tipo del documento
País de afiliación
Intervalo de año de publicación
1.
PLoS Genet ; 6(6): e1001000, 2010 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-20585624

RESUMEN

Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l) gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease.


Asunto(s)
Cardiomiopatía Dilatada/genética , GTP Fosfohidrolasas/genética , Genes Mitocondriales , Predisposición Genética a la Enfermedad , Proteínas Asociadas a Microtúbulos/genética , Mutación , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Cardiomiopatía Dilatada/congénito , Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/patología , Dinaminas , Embrión de Mamíferos/metabolismo , Embrión de Mamíferos/patología , GTP Fosfohidrolasas/química , GTP Fosfohidrolasas/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Microscopía Electrónica de Transmisión , Proteínas Asociadas a Microtúbulos/química , Proteínas Asociadas a Microtúbulos/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Cuaternaria de Proteína , Alineación de Secuencia
2.
PLoS One ; 5(2): e9137, 2010 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-20161761

RESUMEN

BACKGROUND: Fibrillins 1 (FBN1) and 2 (FBN2) are components of microfibrils, microfilaments that are present in many connective tissues, either alone or in association with elastin. Marfan's syndrome and congenital contractural arachnodactyly (CCA) result from dominant mutations in the genes FBN1 and FBN2 respectively. Patients with both conditions often present with specific muscle atrophy or weakness, yet this has not been reported in the mouse models. In the case of Fbn1, this is due to perinatal lethality of the homozygous null mice making measurements of strength difficult. In the case of Fbn2, four different mutant alleles have been described in the mouse and in all cases syndactyly was reported as the defining phenotypic feature of homozygotes. METHODOLOGY/PRINCIPAL FINDINGS: As part of a large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we identified a mouse mutant, Mariusz, which exhibited muscle weakness along with hindlimb syndactyly. We identified an amber nonsense mutation in Fbn2 in this mouse mutant. Examination of a previously characterised Fbn2-null mutant, Fbn2(fp), identified a similar muscle weakness phenotype. The two Fbn2 mutant alleles complement each other confirming that the weakness is the result of a lack of Fbn2 activity. Skeletal muscle from mutants proved to be abnormal with higher than average numbers of fibres with centrally placed nuclei, an indicator that there are some regenerating muscle fibres. Physiological tests indicated that the mutant muscle produces significantly less maximal force, possibly as a result of the muscles being relatively smaller in Mariusz mice. CONCLUSIONS: These findings indicate that Fbn2 is involved in integrity of structures required for strength in limb movement. As human patients with mutations in the fibrillin genes FBN1 and FBN2 often present with muscle weakness and atrophy as a symptom, Fbn2-null mice will be a useful model for examining this aspect of the disease process further.


Asunto(s)
Miembro Posterior/metabolismo , Proteínas de Microfilamentos/genética , Debilidad Muscular/genética , Mutación , Alelos , Animales , Secuencia de Bases , Análisis Mutacional de ADN , Etilnitrosourea/toxicidad , Femenino , Fibrilina-1 , Fibrilina-2 , Fibrilinas , Genotipo , Miembro Posterior/patología , Miembro Posterior/fisiopatología , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/deficiencia , Debilidad Muscular/fisiopatología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Mutagénesis/efectos de los fármacos , Fenotipo , Sindactilia/genética , Sindactilia/patología , Sindactilia/fisiopatología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA