The Bloomsbury Colleges | PhD Studentships | Studentships 2011 | The Effect of Missense Mutations on the Role of Fukutin Related Protein (FKRP)
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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. In addition to muscle pathology and cell biology, the student will gain experience in the techniques of molecular (cloning and expression) and structural biology (crystallisation), and biophysics (circular dichroism spectroscopy), and bioinformatics and how they may be used in translational research.

References:

1.    M. R. Ackroyd, L. Skordis, M. Kaluarachchi, J., Godwin, S., Prior,1., M. Fidanboylu, R. J. Piercy, F. Muntoni and S. C. Brown (2009) Reduced expression of fukutin related protein (FKRP) in mice results in a model for FKRP related muscular dystrophies. Brain 132:439-451.

2.    Wallace, B.A. (2009) Protein Characterisation by Synchrotron Radiation Circular Dichroism Spectroscopy. Quarterly Reviews of Biophysics 42:317-370.

3.    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.

4.    Cowieson, N.P., Miles, A.J., Robin, G., Forwood, J.K., Kobe, B., Martin, J.L., and Wallace, B.A. (2008)  Evaluating Protein: Protein Complex Formation using Synchrotron Radiation Circular Dichroism Spectroscopy. Proteins: Structure Function Bioinformatics   70:1142-1146.

Candidates (UK/EU only) should have, or expect to achieve, a first class or upper second BSc (Hons) degree in a relevant discipline.

Closing date: 18th July 2011. Interviews will be held betweem 22nd-29th July 2011. Start date: October 2011.

Please contact Dr Susan C. Brown, scbrown@rvc.ac.uk, or Prof Bonnie Wallace, b.wallace@mail.cryst.bbk.ac.uk for more details.

How to Apply:

Completed Postgraduate Application Forms should be sent to:

The Graduate School

The Royal Veterinary College

Royal College Street

London NW1 0TU

UK

With their application, candidates are required to submit:

A curriculum vitae (CV)

Two confidential references

Copies of degree certificates

Certified transcript of undergraduate degree

Personal statement detailing their suitability for the project, motivations and intentions

When applying, please indicate where you found out about this studentship (please state the publication title/ web address).

Closing date for applications: This studentship is now closed.