Mutations in the TGF-ß repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm.
Nat Genet
; 44(11): 1249-54, 2012 Nov.
Article
en En
| MEDLINE
| ID: mdl-23023332
ABSTRACT
Elevated transforming growth factor (TGF)-ß signaling has been implicated in the pathogenesis of syndromic presentations of aortic aneurysm, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). However, the location and character of many of the causal mutations in LDS intuitively imply diminished TGF-ß signaling. Taken together, these data have engendered controversy regarding the specific role of TGF-ß in disease pathogenesis. Shprintzen-Goldberg syndrome (SGS) has considerable phenotypic overlap with MFS and LDS, including aortic aneurysm. We identified causative variation in ten individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-ß activity. Cultured dermal fibroblasts from affected individuals showed enhanced activation of TGF-ß signaling cascades and higher expression of TGF-ß-responsive genes relative to control cells. Morpholino-induced silencing of SKI paralogs in zebrafish recapitulated abnormalities seen in humans with SGS. These data support the conclusions that increased TGF-ß signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Aneurisma de la Aorta
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Factor de Crecimiento Transformador beta
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Proteínas Proto-Oncogénicas
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Craneosinostosis
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Proteínas de Unión al ADN
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Aracnodactilia
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Síndrome de Marfan
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Genet
Asunto de la revista:
GENETICA MEDICA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos