The Royal Veterinary College London Biochemistry PhD Studentships 2011

The Graduate School
The Royal Veterinary College
Royal College Street
London NW1 0TU, UK

The Effect Of Missense Mutations On The Role Of Fukutin Related Protein (FKRP)

Lead Supervisor: Dr. Susan C.Brown (RVC)

Co-supervisor: Professor B.A. Wallace (Bbk)

Recently a new mechanism of disease has been identified in the congenital (autosomal recessive) muscular dystrophies that are due to a defect in the glycosylation of alpha dystroglycan. These forms of muscular dystrophy are now known collectively as the dystroglycanopathies. To date mutations in six genes encoding either known or putative glycosyltransferases have been associated with this group of diseases. However, the one most frequently associated with mutations in the Caucasian population is fukutin related protein or FKRP (in Denmark the heterozygote frequency is 1:200). Patients typically show a wide range of clinical features, including severe structural brain involvement resembling Walker Warburg Syndrome (WWS) and Muscle Eye Brain disease (MEB), to congenital muscular dystrophy without brain involvement (MDC1C), and adult-onset limb girdle muscular dystrophy (LGMD2I). We already know that clinical severity in the human relates to the specific mutation and that the introduction of missense mutations in the mouse FKRP gene fails to generate a disease phenotype although a down-regulation of FKRP expression does (Ackroyd, Skordis et al. 2009). The present proposal aims to exploit these differences in order to (i) identify those protein interactions which are crucial to FKRP function, and (ii) determine if clinical phenotype relates at least in part to the effect of different mutations on protein folding and a subsequent disruption of protein interactions. If our hypotheses are proved, this work will have identified an important mechanism of disease in the dystroglycanopathies.

Requirements

The candidate will have an interest in the pathogenesis of human neuromuscular disease and protein structure. The project will be based at the Royal Veterinary College where training in muscle pathology will be given. Circular dichroism (CD) spectroscopy and Synchrotron Radiation Circular Dichroism (SRCD) will be undertaken under the supervision of Professor Bonnie Wallace at Birkbeck College who has a particular interest in these techniques and how they may be used to facilitate translational research. This project therefore represents a unique opportunity to combine cellular and biophysical approaches to assess the role of FKRP structure in the pathogenesis of muscular dystrophy.

Key References:

M. R. Ackroyd, L. Skordis, M. Kaluarachchi, J., Godwin, S., Prior,1., M. Fidanboylu,
R. J. Piercy, F. Muntoni and S. C. Brown Reduced expression of fukutin related protein (FKRP) in mice results in a model for FKRP related muscular dystrophies. Brain 132(2), 439-451. 2009.
Wallace, B.A. & Janes, R.W. (2010) Synchrotron Radiation Circular Dichroism (SRCD) Spectroscopy – An Enhanced Method for Examining Protein Conformations and Protein Interactions. Biochemical Society Transactions, 38:861-873.
Evans, P., Wyatt, K., Wistow, G.J., Bateman, O.A., Wallace, B.A., and Slingsby, C. (2004) The P23T Cataract Mutation Causes Loss of Solubility of Folded gD-Crystallin. J. Mol. Biology 343:435-444.
Wallace, B.A. (2008) Evaluating Protein: Protein Complex Formation using Synchrotron Radiation Circular Dichroism Spectroscopy. Proteins: Structure Function Bioinformatics 70:1142-1146.

Further details about the project may be obtained from:

Lead Supervisor: Dr Susan C. Brown, scbrown@rvc.ac.uk, http://www.rvc.ac.uk/Staff/scbrown.cfm; http://www.cnmd.ac.uk/researchgroups/susanbrown

Co-Supervisor: Prof Bonnie Wallace, b.wallace@mail.cryst.bbk.ac.uk; http://people.cryst.bbk.ac.uk/~ubcg25a/

Further information about PhDs at RVC is available from:

Royal Veterinary College Graduate School: http://www.rvc.ac.uk/Postgraduate/Index.cfm

Application forms and details about how to apply are available from:

http://www.rvc.ac.uk/Postgraduate/Documents/PG08_Forms.pdf

Professor Fiona Cunningham, VBS, fcunning@rvc.ac.uk