title: Disease-associated mutations in L1 CAM interfere with ligand interactions and cell-surface expression.
abstract: 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.
authors.affiliation: Cambridge Institute for Medical Research and Cambridge University Department of Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: De Angelis
authors.forename: Alex
authors.initials: A
authors.lastname: Watkins
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfer
authors.forename: Thomas
authors.initials: T
authors.lastname: Brümmendorf
authors.forename: Sue
authors.initials: S
authors.lastname: Kenwrick
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells; D002448:Cell Adhesion; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D058969:Contactin 2; D017931:DNA Primers / Q000737:chemistry; D017353:Gene Deletion; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics*; D039841:Leukocyte L1 Antigen Complex; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D016296:Mutagenesis; D020125:Mutation, Missense / Q000235:genetics*; D019006:Neural Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D021381:Protein Transport / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D014960:X Chromosome
chemical_list: D000954:Antigens, Surface; C548674:CNTN2 protein, human; D015816:Cell Adhesion Molecules, Neuronal; D058969:Contactin 2; D017931:DNA Primers; D039841:Leukocyte L1 Antigen Complex; D008024:Ligands; D008562:Membrane Glycoproteins; D019006:Neural Cell Adhesion Molecules; D011994:Recombinant Proteins