Pathological missense mutations of neural cell adhesion molecule L1 affecthemophilic and heterophilic binding activities

Mutations in the gene for neural cell adhesion molecule L1 (LICAM) result i n a debilitating, X-linked congenital disorder of brain development. At the neuronal cell surface L1 may interact with a variety of different molecule s including itself and two other CAMs of the immunoglobulin superfamily, ax onin-1 and FI1, However, whether all of these interactions are relevant to normal or abnormal development has not been determined. Over one-third of p atient mutations are single amino acid changes distributed across 10 extrac ellular L1 domains. We ha re studied the effects of 12 missense mutations o n binding to L1, axonin-1 and F11. and shown for the first time that wherea s many mutations affect all three interactions, others affect hemophilic or heterophilic binding alone. Patient pathology is therefore due to differen t types of L1 malfunction. The nature and functional consequence of mutatio n is also reflected in the severity of the resultant phenotype with structu ral mutations likely to affect more than one binding activity and result in early mortality. Moreover, the data indicate that several extracellular do mains of L1 are required for hemophilic and heterophilic interactions.