English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  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

Basic

show hide
Genre: Journal Article
Alternative Title : Hum Mol Gen

Files

show Files

Locators

show

Creators

show
hide
 Creators:
Albrecht, Andrea N.1, Author              
Kornak, Uwe1, Author              
Böddrich, Annett2, Author              
Süring, Kathrin3, Author
Robinson, Peter N.1, Author              
Stiege, Asita C.1, Author              
Lurz, Rudi3, Author
Stricker, Siegmar1, Author              
Wanker, Erich E.3, Author
Mundlos, Stefan1, Author              
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              

Content

show
hide
Free keywords: -
 Abstract: 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

show
hide
Language(s): eng - English
 Dates: 2004-10-15
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: eDoc: 228694
DOI: 10.1093/hmg/ddh277
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Human Molecular Genetics
  Alternative Title : Hum Mol Gen
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 13 (20) Sequence Number: - Start / End Page: 2351 - 2359 Identifier: ISSN: 0964-6906