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Human Molecular Genetics, 2002, Vol. 11, No. 1 1-12
© 2002 Oxford University Press

Disease-associated mutations in L1 CAM interfere with ligand interactions and cell-surface expression

Elena De Angelis, Alex Watkins, Michael Schäfer1, Thomas Brümmendorf1 and Sue Kenwrick+

Cambridge Institute for Medical Research and Cambridge University Department of Medicine, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2XY, UK and 1Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13092 Berlin, Germany

Mutations in the L1CAM gene cause a highly variable neurological disease described as X-linked hydrocephalus, MASA syndrome or spastic paraplegia type I. Over one-third of the mutations identified in affected boys are missense, unique to individual families and distributed primarily across the large extracellular domain of the L1 protein. We have examined the effects of 25 missense mutations on binding to homophilic (L1) and heterophilic (TAX-1) ligands as well as on intracellular trafficking. All but three of these result in reduced ligand binding or impaired movement to the surface of COS and CHO cells. Therefore, we demonstrate for the first time that most missense mutations found in affected families have functional consequences. Furthermore, mutations that are predicted to affect the structure of individual extracellular domains are more likely to affect intracellular processing and/or ligand binding than those mutations affecting surface properties of the molecule.

+ To whom correspondence should be addressed. Tel: +44 1223 762616; Fax: +44 1223 331206; Email: sjk12@mole.bio.cam.ac.uk


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