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          Institute: MPI für molekulare Genetik     Collection: Research Group Development and Disease     Display Documents



  history
ID: 456438.0, MPI für molekulare Genetik / Research Group Development and Disease
A gradient of ROR2 protein stability and membrane
localization confers brachydactyly type B or Robinow syndrome phenotypes
Authors:Schwarzer, Wibke; Witte, Florian; Rajab, Anna; Mundlos, Stefan; Stricker, Sigmar
Language:English
Date of Publication (YYYY-MM-DD):2009-11
Title of Journal:Human Molecular Genetics
Journal Abbrev.:Hum Mol Genet
Volume:18
Issue / Number:21
Start Page:4013
End Page:4021
Copyright:© The Author 2009
Review Status:not specified
Audience:Experts Only
Abstract / Description: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.
Comment of the Author/Creator:email: stefan.mundlos@charite.de
External Publication Status:published
Document Type:Article
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:Institute for Medical Genetics, Charite and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), University Medicine Berlin, Germany
Genetic Unit, DGHA, Ministry of Health, Muscat, Sultanate of Oman
Identifiers:DOI:10.1093/hmg/ddp345
ISSN:0964-6906
URL:http://hmg.oxfordjournals.org/cgi/reprint/18/21/40...
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