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Pathological missense mutations of neural cell adhesion molecule L1 affect homophilic and heterophilic binding activities
Author(s) -
De Angelis Elena,
MacFarlane John,
Du JianSheng,
Yeo Giles,
Hicks Ray,
Rathjen Fritz G.,
Kenwrick Sue,
Brümmendorf Thomas
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.17.4744
Subject(s) - missense mutation , biology , mutation , phenotype , cell adhesion molecule , l1 , neural cell adhesion molecule , cell adhesion , immunoglobulin superfamily , genetics , extracellular , mutant , gene , microbiology and biotechnology , cell
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.