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  A gradient of ROR2 protein stability and membrane localization confers brachydactyly type B or Robinow syndrome phenotypes

Schwarzer, W., Witte, F., Rajab, A., Mundlos, S., & Stricker, S. (2009). A gradient of ROR2 protein stability and membrane localization confers brachydactyly type B or Robinow syndrome phenotypes. Human Molecular Genetics, 18(21), 4013-4021. doi:10.1093/hmg/ddp345.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7CDE-F Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7CDF-D
Genre: Journal Article
Alternative Title : Hum Mol Genet

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 Creators:
Schwarzer, Wibke1, Author              
Witte, Florian2, Author              
Rajab, Anna, Author
Mundlos, Stefan1, Author              
Stricker, Sigmar1, Author              
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              

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 Abstract: Mutations in ROR2 cause dominant brachydactyly type B (BDB1) or recessive Robinow syndrome (RRS), each characterized by a distinct combination of phenotypic features. We here report a novel nonsense mutation in ROR2 (c.1324C>T; p.R441X) causing intracellular protein truncation in a patient exhibiting features of RRS in conjunction with severe recessive brachydactyly. The mutation is located at the same position as a previously described frame shift mutation causing dominant BDB1. To investigate the apparent discrepancy in phenotypic outcome, we analysed ROR2 protein stability and distribution in stably transfected cell lines expressing exact copies of several human RRS and BDB1 intracellular mutations. RRS mutant proteins were less abundant and retained intracellularly, although BDB1 mutants were stable and predominantly located at the cell membrane. The p.R441X mutation showed an intermediate pattern with membrane localization but also high endoplasmic reticulum retention. Furthermore, we observed a correlation between the severity of BDB1, the location of the mutation, and the amount of membrane-associated ROR2. Membrane protein fraction quantification revealed a gradient of distribution and stability correlating with the clinical phenotypes. This gradual model was confirmed by crossing mouse models for RRS and BDB1, yielding double heterozygous animals that exhibited an intermediate phenotype. We propose a model in which the RRS versus the BDB1 phenotype is determined by the relative degree of protein retention/ degradation and the amount of mutant protein reaching the plasma membrane.

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Language(s): eng - English
 Dates: 2009-11
 Publication Status: Published in print
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Title: Human Molecular Genetics
  Alternative Title : Hum Mol Genet
Source Genre: Journal
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Pages: - Volume / Issue: 18 (21) Sequence Number: - Start / End Page: 4013 - 4021 Identifier: ISSN: 0964-6906