Pathological missense mutations of neural cell adhesion molecule L1 affect homophilic and heterophilic binding activities
- PMID: 10469653
- PMCID: PMC1171547
- DOI: 10.1093/emboj/18.17.4744
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.
Similar articles
-
Genetic and clinical aspects of X-linked hydrocephalus (L1 disease): Mutations in the L1CAM gene.Hum Mutat. 2001;18(1):1-12. doi: 10.1002/humu.1144. Hum Mutat. 2001. PMID: 11438988 Review.
-
L1 mediated homophilic binding and neurite outgrowth are modulated by alternative splicing of exon 2.J Neurobiol. 2002 Jun 5;51(3):177-89. doi: 10.1002/neu.10052. J Neurobiol. 2002. PMID: 11984840
-
Disease-associated mutations in L1 CAM interfere with ligand interactions and cell-surface expression.Hum Mol Genet. 2002 Jan 1;11(1):1-12. doi: 10.1093/hmg/11.1.1. Hum Mol Genet. 2002. PMID: 11772994
-
X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene.Nat Genet. 1994 Jul;7(3):402-7. doi: 10.1038/ng0794-402. Nat Genet. 1994. PMID: 7920659
-
[X-linked hydrocephalus syndrome].Ryoikibetsu Shokogun Shirizu. 2000;(30 Pt 5):47-8. Ryoikibetsu Shokogun Shirizu. 2000. PMID: 11057138 Review. Japanese. No abstract available.
Cited by
-
Fast turnover of L1 adhesions in neuronal growth cones involving both surface diffusion and exo/endocytosis of L1 molecules.Mol Biol Cell. 2007 Aug;18(8):3131-43. doi: 10.1091/mbc.e06-12-1101. Epub 2007 May 30. Mol Biol Cell. 2007. PMID: 17538021 Free PMC article.
-
LAD-1, the Caenorhabditis elegans L1CAM homologue, participates in embryonic and gonadal morphogenesis and is a substrate for fibroblast growth factor receptor pathway-dependent phosphotyrosine-based signaling.J Cell Biol. 2001 Aug 20;154(4):841-55. doi: 10.1083/jcb.200009004. Epub 2001 Aug 13. J Cell Biol. 2001. PMID: 11502758 Free PMC article.
-
Stimulation of glioma cell motility by expression, proteolysis, and release of the L1 neural cell recognition molecule.Cancer Cell Int. 2009 Oct 29;9:27. doi: 10.1186/1475-2867-9-27. Cancer Cell Int. 2009. PMID: 19874583 Free PMC article.
-
Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins.J Cell Biol. 2001 Nov 12;155(4):661-73. doi: 10.1083/jcb.200101099. Epub 2001 Nov 12. J Cell Biol. 2001. PMID: 11706054 Free PMC article.
-
Differential effects of human L1CAM mutations on complementing guidance and synaptic defects in Drosophila melanogaster.PLoS One. 2013 Oct 14;8(10):e76974. doi: 10.1371/journal.pone.0076974. eCollection 2013. PLoS One. 2013. PMID: 24155914 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous
