Human Molecular Genetics Advance Access originally published online on October 26, 2006
Human Molecular Genetics 2006 15(23):3436-3445; doi:10.1093/hmg/ddl421
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The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface
1 Unitat de Genètica Molecular, Departament de Genòmica i Proteòmica, Institut de Biomedicina de València-CSIC, València, Spain and 2 Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
* To whom correspondence should be addressed at: Institut de Biomedicina de València-CSIC, Unitat de Genètica Molecular, C/Jaume Roig, 11, E46010 València, Spain. Tel: +34 963391755; Fax: +34 963393774; Email: jpereztur{at}ibv.csic.es
Received July 19, 2006; Accepted October 20, 2006
Autosomal dominant lateral temporal epilepsy (ADTLE) is a partial epilepsy caused by mutations in LGI1, a multidomain protein of unknown function. To begin to understand the biological function of LGI1, we have determined its pattern of glycosylation, subcellular expression and capacity for secretion. LGI1 is expressed as two different isoforms in the brain, and we show that the long isoform is a secreted protein, whereas the short isoform is retained in an intracellular pool. ADLTE-related mutants of the long form are defective for secretion and are retained in the endoplasmic reticulum and Golgi complex. Finally, we show that normal secreted LGI1 specifically binds to the cell surface of differentiated PC12 cells. We propose that LGI1 is a secreted factor important for neuronal development and that ADTLE is a disease that results from the loss of regulation in the protein available either extracellular or intracellularly.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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