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: Elena De Angelis, Alex Watkins, Michael Schäfer, Thomas Brümmendorf, Sue Kenwrick
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 11 Issue 1 Pg. 1-12 (Jan 01 2002) ISSN: 0964-6906 [Print] England
• PMID: 11772994 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Surface
• CNTN2 protein, human
• Cell Adhesion Molecules, Neuronal
• Contactin 2
• DNA Primers
• Leukocyte L1 Antigen Complex
• Ligands
• Membrane Glycoproteins
• Neural Cell Adhesion Molecules
• Recombinant Proteins

Topics

• Animals
• Antigens, Surface (genetics, metabolism)
• COS Cells
• Cell Adhesion
• Cell Adhesion Molecules, Neuronal (genetics, metabolism)
• Cell Membrane (metabolism)
• Contactin 2
• DNA Primers (chemistry)
• Gene Deletion
• Humans
• Hydrocephalus (genetics)
• Leukocyte L1 Antigen Complex
• Ligands
• Male
• Membrane Glycoproteins (genetics, metabolism)
• Mutagenesis
• Mutation, Missense (genetics)
• Neural Cell Adhesion Molecules (genetics, metabolism)
• Polymerase Chain Reaction
• Protein Binding
• Protein Transport (physiology)
• Recombinant Proteins (metabolism)
• X Chromosome