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1.
Genet Med ; 17(4): 291-9, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25122145

RESUMEN

PURPOSE: The aim of this study was to identify the genetic cause of early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy in a consanguineous family. METHODS: An affected 6-month-old child underwent neurological and ophthalmological examinations. Genetic analyses included homozygosity mapping, copy number analysis, conventional polymerase chain reaction, Sanger sequencing, quantitative polymerase chain reaction, and whole-exome sequencing. Expression analysis of GRID2 was performed by quantitative polymerase chain reaction and immunohistochemistry. RESULTS: A homozygous deletion of exon 2 of GRID2 (p.Gly30_Glu81del) was identified in the proband. GRID2 encodes an ionotropic glutamate receptor known to be selectively expressed in cerebellar Purkinje cells. Here, we demonstrated GRID2 expression in human adult retina and retinal pigment epithelium. In addition, Grid2 expression was demonstrated in different stages of murine retinal development. GRID2 immunostaining was shown in murine and human retina. Whole-exome sequencing in the proband did not provide arguments for other disease-causing mutations, supporting the idea that the phenotype observed represents a single clinical entity. CONCLUSION: We identified GRID2 as an underlying disease gene of early-onset autosomal recessive cerebellar ataxia with retinal dystrophy, expanding the clinical spectrum of GRID2 deletion mutants. We demonstrated for the first time GRID2 expression and localization in human and murine retina, providing evidence for a novel functional role of GRID2 in the retina.


Asunto(s)
Receptores de Glutamato/genética , Distrofias Retinianas/genética , Degeneraciones Espinocerebelosas/genética , Animales , Preescolar , Variaciones en el Número de Copia de ADN/genética , Exones/genética , Femenino , Regulación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Ratones , Linaje , Receptores de Glutamato/biosíntesis , Retina/metabolismo , Retina/patología , Distrofias Retinianas/complicaciones , Distrofias Retinianas/patología , Eliminación de Secuencia , Degeneraciones Espinocerebelosas/complicaciones , Degeneraciones Espinocerebelosas/patología
2.
Anticancer Res ; 32(7): 2551-61, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22753713

RESUMEN

AIM: To evaluate the impact of heat-shock protein 90 (HSP90) blockade by the novel inhibitor NVP-AUY922, on tumor growth and angiogenesis in pancreatic cancer. MATERIALS AND METHODS: Effects of NVP-AUY922 on signaling pathways were evaluated by western blotting. Cell motility of cancer cells, pericytes and endothelial cells was investigated in Boyden chambers. Impact of HSP90 blockade on pancreatic tumor growth and angiogenesis were studied in in vivo tumor models. RESULTS: NVP-AUY922 effectively inhibited cancer cell growth. Moreover, HSP90 inhibition potently interfered with multiple signaling pathways in cancer cells, as well as endothelial cells and pericytes, leading to significant reduction of pro-migratory and invasive properties of these cell types. In vivo, treatment with NVP-AUY922 significantly inhibited growth and vascularization of pancreatic cancer at doses far below the maximum tolerated dose. CONCLUSION: HSP90 blockade by the novel synthetic inhibitor NVP-AUY922 effectively reduces pancreatic cancer progression through direct effects on cancer cells, as well as on endothelial cells and pericytes.


Asunto(s)
Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Isoxazoles/farmacología , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/tratamiento farmacológico , Resorcinoles/farmacología , Animales , Comunicación Celular/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Terapia Molecular Dirigida , Neovascularización Patológica/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Distribución Aleatoria , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
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