title: Pathological missense mutations of neural cell adhesion molecule L1 affect homophilic and heterophilic binding activities.
abstract: Mutations in the gene for neural cell adhesion molecule L1 (L1CAM) result in a debilitating X-linked congenital disorder of brain development. At the neuronal cell surface L1 may interact with a variety of different molecules including itself and two other CAMs of the immunoglobulin superfamily, axonin-1 and F11. However, whether all of these interactions are relevant to normal or abnormal development has not been determined. Over one-third of patient mutations are single amino acid changes distributed across 10 extracellular L1 domains. We have studied the effects of 12 missense mutations on binding to L1, axonin-1 and F11 and shown for the first time that whereas many mutations affect all three interactions, others affect homophilic or heterophilic binding alone. Patient pathology is therefore due to different types of L1 malfunction. The nature and functional consequence of mutation is also reflected in the severity of the resultant phenotype with structural mutations likely to affect more than one binding activity and result in early mortality. Moreover, the data indicate that several extracellular domains of L1 are required for homophilic and heterophilic interactions.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge Clinical School, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: E
authors.initials: E
authors.lastname: De Angelis
authors.forename: J
authors.initials: J
authors.lastname: MacFarlane
authors.forename: J S
authors.initials: JS
authors.lastname: Du
authors.forename: G
authors.initials: G
authors.lastname: Yeo
authors.forename: R
authors.initials: R
authors.lastname: Hicks
authors.forename: F G
authors.initials: FG
authors.lastname: Rathjen
authors.forename: S
authors.initials: S
authors.lastname: Kenwrick
authors.forename: T
authors.initials: T
authors.lastname: Brümmendorf
mesh_terms: D000818:Animals; D019556:COS Cells; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D058969:Contactin 2; D058966:Contactins; D008040:Genetic Linkage; D006226:Hand Deformities / Q000235:genetics; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics; D008607:Intellectual Disability / Q000235:genetics; D039841:Leukocyte L1 Antigen Complex; D008562:Membrane Glycoproteins / Q000235:genetics*; D008954:Models, Biological; D008957:Models, Genetic; D016296:Mutagenesis; D020125:Mutation, Missense; D019006:Neural Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D010264:Paraplegia / Q000235:genetics; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014960:X Chromosome
chemical_list: C548674:CNTN2 protein, human; D015816:Cell Adhesion Molecules, Neuronal; D058969:Contactin 2; D058966:Contactins; D039841:Leukocyte L1 Antigen Complex; D008562:Membrane Glycoproteins; D019006:Neural Cell Adhesion Molecules; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins