Deutsch
 
Hilfe Datenschutzhinweis Impressum
  DetailsucheBrowse

Datensatz

DATENSATZ AKTIONENEXPORT
  A molecular pathogenesis for transcription factor associated poly-alanine tract expansions

Albrecht, A. N., Kornak, U., Böddrich, A., Süring, K., Robinson, P. N., Stiege, A. C., et al. (2004). A molecular pathogenesis for transcription factor associated poly-alanine tract expansions. Human Molecular Genetics, 13(20), 2351-2359. doi:10.1093/hmg/ddh277.

Item is

Basisdaten

einblenden: ausblenden:
Genre: Zeitschriftenartikel
Alternativer Titel : Hum Mol Gen

Externe Referenzen

einblenden:

Urheber

einblenden:
ausblenden:
 Urheber:
Albrecht, Andrea N.1, Autor           
Kornak, Uwe1, Autor           
Böddrich, Annett2, Autor           
Süring, Kathrin3, Autor
Robinson, Peter N.1, Autor           
Stiege, Asita C.1, Autor           
Lurz, Rudi3, Autor
Stricker, Siegmar1, Autor           
Wanker, Erich E.3, Autor
Mundlos, Stefan1, Autor           
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              
3Max Planck Society, ou_persistent13              

Inhalt

einblenden:
ausblenden:
Schlagwörter: -
 Zusammenfassung: Poly-alanine (Ala) tract expansions in transcription factors have been shown to be associated with human birth defects such as malformations of the brain, the digits, and other structures. Expansions of a poly-Ala tract from 15 to 22 (+7)-29 (+14) Ala in Hoxd13, for example, result in the limb malformation synpolydactyly in humans and in mice [synpolydactyly homolog (spdh)]. Here, we show that an increase of the Ala repeat above a certain length (22 Ala) is associated with a shift in the localization of Hoxd13 from nuclear to cytoplasmic, where it forms large amorphous aggregates. We observed similar aggregates for expansion mutations in SOX3, RUNX2 and HOXA13, pointing to a common mechanism. Cytoplasmic aggregation of mutant Hoxd13 protein is influenced by the length of the repeat, the level of expression and the efficacy of degradation by the proteasome. Heat shock proteins Hsp70 and Hsp40 co-localize with the aggregates and activation of the chaperone system by geldanamycin leads to a reduction of aggregate formation. Furthermore, recombinant mutant Hoxd13 protein forms aggregates in vitro demonstrating spontaneous misfolding of the protein. We analyzed the mouse mutant spdh, which harbors a +7 Ala expansion in Hoxd13 similar to the human synpolydactyly mutations, as an in vivo model and were able to show a reduction of mutant Hoxd13 and, in contrast to wt Hoxd13, a primarily cytoplasmic localization of the protein. Our results provide evidence that poly-Ala repeat expansions in transcription factors result in misfolding, degradation and cytoplasmic aggregation of the mutant proteins.

Details

einblenden:
ausblenden:
Sprache(n): eng - English
 Datum: 2004-10-15
 Publikationsstatus: Erschienen
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: eDoc: 228694
DOI: 10.1093/hmg/ddh277
 Art des Abschluß: -

Veranstaltung

einblenden:

Entscheidung

einblenden:

Projektinformation

einblenden:

Quelle 1

einblenden:
ausblenden:
Titel: Human Molecular Genetics
  Alternativer Titel : Hum Mol Gen
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 13 (20) Artikelnummer: - Start- / Endseite: 2351 - 2359 Identifikator: ISSN: 0964-6906