A missense mutation in podocin leads to early and severe renal disease in mice.
Kidney Int
; 73(9): 1038-47, 2008 May.
Article
en En
| MEDLINE
| ID: mdl-18288100
Mutations in the NPHS2 gene, encoding podocin, are responsible for familial autosomal recessive and sporadic cases of steroid-resistant nephrotic syndrome. We have successfully generated a mouse model in which the common p.R138Q mutation found in nephrotic patients is expressed in the kidney. Homozygous mice express the mutant protein, which is mislocated to the cytoplasm, along with a portion of the nephrin pool. These mice die within the first month of life, but their survival depends on the genetic background. Albuminuria manifests early and leads to progressive renal insufficiency, characterized histologically by diffuse mesangiolysis and mesangial sclerosis, endothelial lesions along with podocyte abnormalities such as widespread foot process effacement. Gene expression profiling revealed marked differences between these and the podocin-null mice, including significant perturbations of podocyte-expressed genes such as Cd2ap, Vegfa and the transcription factors Lmx1b and Zhx2. Upregulation of Serpine1 and Tgfb1 implicates these as potential mediators of disease progression in these mice. This mouse model of nephrotic syndrome may serve as a valuable tool in studies of in vivo intracellular protein trafficking of podocyte proteins, as well as testing therapeutic modalities aimed at correcting the targeting of mutant proteins.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Mutación Missense
/
Péptidos y Proteínas de Señalización Intracelular
/
Proteínas de la Membrana
/
Síndrome Nefrótico
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Kidney Int
Año:
2008
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Estados Unidos