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Human Molecular Genetics Advance Access published online on July 27, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi259
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received May 9, 2005
Revised July 12, 2005
Accepted July 20, 2005

Article

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

Ying Chen 1, William P. Bellamy 1, Miguel C. Seabra 1, Mark C. Field 2, and Bassam R. Ali 3*

1 Division of Biomedical Sciences, Faculty of Medicine, Imperial College, London SW7 2AZ, UK
2 The Molteno Building, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
3 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

* To whom correspondence should be addressed.
Bassam R. Ali, E-mail: b.ali{at}imperial.ac.uk


  Abstract

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 are rejected by an ER quality control system and targeted for degradation. In some cases only a minor fraction of nascent chains are 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 compared to 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 if our analysis had identified new ER-degradation substrates we established that ER retention is indeed the mechanism underlying Robinow syndrome, one of the identified candidates. Specifically, mutant alleles of ROR2 that are associated with Robinow syndrome are retained within the ER, whilst wild-type and non-pathogenic alleles are exported to the plasma membrane. These data both uncover a major pathogenic factor for Robinow syndrome and also indicate that misfolding of secretory proteins is likely to contribute significantly to human disease and morbidity.


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