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1.
Nat Genet ; 39(7): 875-81, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17558409

RESUMEN

Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) syndrome belong to the group of developmental autosomal recessive disorders that are associated with primary cilium dysfunction. Using SNP mapping, we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS, and we show that inactivation of the mouse ortholog Rpgrip1l (Ftm) recapitulates the cerebral, renal and hepatic defects of CORS and MKS. In addition, we show that RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4, known genes associated with MKS, CORS and nephronophthisis (a related renal disorder and ciliopathy). In addition, the RPGRIP1L missense mutations found in CORS individuals diminishes the interaction between RPGRIP1L and nephrocystin-4. Our findings show that mutations in RPGRIP1L can cause the multiorgan phenotypic abnormalities found in CORS or MKS, which therefore represent a continuum of the same underlying disorder.


Asunto(s)
Enfermedades Cerebelosas/genética , Trastornos de la Motilidad Ciliar/genética , Encefalocele/genética , Oftalmopatías/genética , Enfermedades Renales/genética , Proteínas/genética , Animales , Niño , Proteínas del Citoesqueleto , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Ratones Mutantes , Mutación Puntual , Síndrome
2.
Nature ; 458(7240): 894-8, 2009 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-19234441

RESUMEN

Several independent, genome-wide association studies have identified a strong correlation between body mass index and polymorphisms in the human FTO gene. Common variants in the first intron define a risk allele predisposing to obesity, with homozygotes for the risk allele weighing approximately 3 kilograms more than homozygotes for the low risk allele. Nevertheless, the functional role of FTO in energy homeostasis remains elusive. Here we show that the loss of Fto in mice leads to postnatal growth retardation and a significant reduction in adipose tissue and lean body mass. The leanness of Fto-deficient mice develops as a consequence of increased energy expenditure and systemic sympathetic activation, despite decreased spontaneous locomotor activity and relative hyperphagia. Taken together, these experiments provide, to our knowledge, the first direct demonstration that Fto is functionally involved in energy homeostasis by the control of energy expenditure.


Asunto(s)
Obesidad/genética , Oxo-Ácido-Liasas/deficiencia , Oxo-Ácido-Liasas/metabolismo , Delgadez/genética , Tejido Adiposo/metabolismo , Adiposidad/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Animales , Animales Recién Nacidos , Peso Corporal/genética , Encéfalo/metabolismo , Ingestión de Alimentos/fisiología , Embrión de Mamíferos/anatomía & histología , Embrión de Mamíferos/embriología , Metabolismo Energético/genética , Metabolismo Energético/fisiología , Femenino , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/fisiopatología , Homocigoto , Hiperfagia/genética , Insulina/metabolismo , Masculino , Ratones , Oxigenasas de Función Mixta , Actividad Motora/genética , Actividad Motora/fisiología , Obesidad/prevención & control , Oxo-Ácido-Liasas/genética , Fenotipo , Sistema Nervioso Simpático/fisiología
3.
Development ; 134(14): 2569-77, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17553904

RESUMEN

In this study we show in mice that Ftm (Rpgrip1l) is located at the ciliary basal body. Our data reveal that Ftm is necessary for developmental processes such as the establishment of left-right asymmetry and patterning of the neural tube and the limbs. The loss of Ftm affects the ratio of Gli3 activator to Gli3 repressor, suggesting an involvement of Ftm in Shh signalling. As Ftm is not essential for cilia assembly but for full Shh response, Ftm can be considered as a novel component for cilium-related Hh signalling. Furthermore, the absence of Ftm in arthropods underlines the divergence between vertebrate and Drosophila Hh pathways.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Tipificación del Cuerpo/fisiología , Cilios/metabolismo , Proteínas Hedgehog/metabolismo , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales/química , Animales , Células Cultivadas , Embrión de Mamíferos/metabolismo , Extremidades/embriología , Extremidades/crecimiento & desarrollo , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Ratones Noqueados , Mutación , Proteínas del Tejido Nervioso/metabolismo , Defectos del Tubo Neural/genética , Defectos del Tubo Neural/metabolismo , Fenotipo , Polidactilia/genética , Polidactilia/metabolismo , Proteína Gli3 con Dedos de Zinc
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