Human Molecular Genetics, 2002, Vol. 11, No. 26 3319-3331
© 2002 Oxford University Press
Functional requirements for fukutin-related protein in the Golgi apparatus
1Department of Pharmacology, University of Oxford, Oxford, UK, 2Institute for Physiological Chemistry, University of Mainz, Mainz, Germany and 3The Dubowitz Neuromuscular Centre, Department of Paediatrics, Imperial College School of Medicine, Hammersmith Hospital Campus, London, UK
Received August 22, 2002; Accepted October 21, 2002
Two forms of congenital muscular dystrophy (CMD), Fukuyama CMD and CMD type 1C (MDC1C) are caused by mutations in the genes encoding two putative glycosyltransferases, fukutin and fukutin-related protein (FKRP). Additionally, mutations in the FKRP gene also cause limb-girdle muscular dystrophy type 2I (LGMD2I), a considerably milder allelic variant than MDC1C. All of these diseases are associated with secondary changes in muscle 
-dystroglycan expression. To elucidate the function of FKRP and fukutin and examine the effects of MDC1C patient mutations, we have determined the mechanism for the subcellular location of each protein. FKRP and fukutin are targeted to the medial-Golgi apparatus through their N-termini and transmembrane domains. Overexpression of FKRP in CHO cells alters the post-translational processing of - and ß-dystroglycan inhibiting maturation of the two isoforms. Mutations in the DxD motif in the putative active site of the protein or in the Golgi-targeting sequence, which cause FKRP to be inefficiently trafficked to the Golgi apparatus, did not alter dystroglycan processing in vitro. The P448L mutation in FKRP that causes congenital muscular dystrophy changes a conserved amino acid resulting in the mislocalization of the mutant protein in the cell that is unable to alter dystroglycan processing. Our data show that FKRP and fukutin are Golgi-resident proteins and that FKRP is required for the post-translational modification of dystroglycan. Aberrant processing of dystroglycan caused by a mislocalized FKRP mutant could be a novel mechanism that causes congenital muscular dystrophy.
* To whom correspondence should be addressed at: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK. Tel: +44 01865271860; Fax: +44 01865271853; Email: dblake{at}enterprise.molbiol.ox.ac.uk
Present address: National Blood Service, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
The authors wish it to be known that, in their opinion, these two authors should be considered as joint First Authors.
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