L1 Signalling

In 1991 we published the sequence for the human L1 cDNA. The gene for L1 is located on the X-chromosome and had previously been identified as a candidate gene for X-linked hydrocephalus and MASA syndrome. We were unaware of this but were contacted by both Sue Kenwrick in Cambridge and Patrick Willems in Antwerp. These human geneticists used our cDNA as a probe to analyze a number of families and confirmed that mutations in L1 caused these inherited diseases.

We decided to apply our ideas about L1 function to an analysis of the mutations in L1 and correlate them with different aspects of the diseases. We discovered that mutations in the L1 cytoplasmic domain are most often less severe than other mutations abut that they lead to defects consistent with failures of axon guidance. In contrast mutations that would lead to a loss of L1 expression or expression of markedly truncated form are most sever and often lead to death before the first year of life is complete (Yamasaki et al, 1997). The unpublished details of this paper are available at this web site Yamasaki et al.. We also reported that mutations of key residues that control protein folding are more severe than mutations affecting surface residues (Kamiguchi et al, 1998). These findings were subsequently confirmed by other investigators.

There are several web sites devoted to information about X-linked hydrocephalus. This include sites at the University of Antwerp, NIH and the U.K.

Two labs have made knock-out mice for L1. A number of labs have analyzed various aspects of the CNS and PNS of these mice and there is general agreement on the phenotype. There is a remarkable similarity to X-linked hydrocephalus. For example agenesis of the corpus callosum has been found, abnormal development of the cortico-spinal tract, and abnormal cerebellar development. Our lab has participated in this, studying neurons from L1 knock-out mice in culture and development of the PNS in these mice. We are currently looking at knock-in mice to test hypotheses about the function of different regions of the L1 molecule.

Related Publications

Wong, E.V., Kenwrick, S., Willems, P., Lemmon, V. Mutations in the cell adhesion molecule L1 cause mental retardation. Trends in Neuroscience, 18:168-172, 1995. Download PDF

Fransen, E., Lemmon, V., Van Camp, G., Vits, L., Coucke, P., Willems, P.J. CRASH syndrome: a clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus due to mutations in one single gene, L1. European Journal of Human Genetics. 3:273-284, 1995.

Yamasaki, M., Thompson, P., Lemmon, V. CRASH syndrome: mutations in the L1 gene correlate with severity of the disease. Neuropediatrics, 28:175-178, 1997. Download PDF

Fransen, E., D'Hooge, R., Van Camp, G., Verhoye, M., Sijbers, J., Reyniers, E., Soriano, P., Kamiguchi, H., Willemsen, R., Koekkoek, S.K.E., De Zeeuw, C.I., P. De Deyn, P.P., Van der Linden, A., Lemmon, V., Frank Kooy, R.F., and Willems, P.J. L1 knockout mice show dilated ventricles, vermis hypoplasia and impaired exploration patterns Hum. Mol. Genet, 7:999-1009, 1998

Kamiguchi, H., Hlavin, M.L., Yamasaki, M., Lemmon, V. Adhesion molecules and inherited diseases of the nervous system. Annual Reviews of Neuroscience, 1998, 21:97-125s Download PDF

Kamiguchi, H., Hlavin, M.L., Lemmon, V. Role of L1 in neural development: what the knockouts tell us. Mol. Cell Neurosci. 12:48-55, 1998 Download PDF

Haney, C.A., Sahenk, Z., Li, C., Lemmon, V.P., Roder, J., Trapp, B.D. Heterophilic binding of L1 on unmyelinated sensory axons mediates Schwann cell adhesion and is required for axonal survival. J. Cell Biol. 146:1173-1183, 1999 Download PDF

Kooy,R.F., Verhoye, M., Lemmon, V. and Van Der Linden, A., Analysis of mouse brain by magnetic resonance imaging (MRI), Eur J Hum Genet., in press