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Human Molecular Genetics Advance Access originally published online on July 27, 2005
Human Molecular Genetics 2005 14(17):2559-2569; doi:10.1093/hmg/ddi259
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

ER-associated protein degradation is a common mechanism underpinning numerous monogenic diseases including Robinow syndrome

Ying Chen1, William P. Bellamy1, Miguel C. Seabra1, Mark C. Field2 and Bassam R. Ali1,*

1Division of Biomedical Sciences, Faculty of Medicine, Imperial College, London SW7 2AZ, UK and 2The Molteno Building, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK

* To whom correspondence should be addressed at: Cell and Molecular Biology Section, Division of Biomedical Sciences, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, London SW7 2AZ, UK. Tel: +44 2075943105; Fax: +44 2075943015; Email: b.ali{at}imperial.ac.uk

Received May 9, 2005; Accepted July 12, 2005

Correct folding of nascent polypeptide chains within the ER is critical for function, assembly into multi-subunit complexes and trafficking through the exocytic pathway for secretory and cell surface proteins. This process is rather inefficient, and a substantial proportion of nascent polypeptides is rejected by an ER quality control system and targeted for degradation. In some cases, only a minor fraction of nascent chains is correctly folded, and the smallest alteration to polypeptide primary structure (i.e. point mutation) can result in the complete loss of function with inherent pathological consequences; cystic fibrosis and emphysema result from such mutations. We have taken a bioinformatic approach to parse a large database of known disease susceptibility genes for candidates whose disease-associated alleles are likely prone to misfolding in the ER. Surprisingly, we find that proteins with ER-targeting signals are over represented in this database when compared with all predicted proteins in the human genome (45 versus 30%). We selected a subgroup of proteins that were positive for both an ER-targeting signal and a membrane-anchoring domain and thereby identified several ER-associated degradation diseases candidates. To determine whether our analysis had identified new ER-degradation substrates, we established that ER retention is indeed the mechanism underlying Robinow syndrome (RRS), one of the identified candidates. Specifically, mutant alleles of ROR2 that are associated with RRS are retained within the ER, whereas wild-type and non-pathogenic alleles are exported to the plasma membrane. These data both uncover a major pathogenic factor for RRS and indicate that misfolding of secretory proteins is likely to significantly contribute to human disease and morbidity.


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