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Human Molecular Genetics Advance Access published online on April 27, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi169
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received January 6, 2005
Revised April 19, 2005
Accepted April 19, 2005

Article

ADPEAF Mutations Reduce Levels of Secreted LGI1, a Putative Tumor Suppressor Protein Linked to Epilepsy

Kristen R. Senechal 1, Christina Thaller 2, and Jeffrey L. Noebels 3*

1 Developmental Neurogenetics Laboratory Department of Neurology Baylor College of Medicine One Baylor Plaza Houston, TX 77030
2 Verna and Marrs McLean Department of Biochemistry and Molecular Biology Baylor College of Medicine One Baylor Plaza Houston, Texas 77030; Max Planck Institute of Experimental Endocrinology Feodor-Lynen-Strasse 7 30625 Hannover, Germany
3 Developmental Neurogenetics Laboratory Department of Neurology Baylor College of Medicine One Baylor Plaza Houston, TX 77030; Department of Neuroscience Baylor College of Medicine One Baylor Plaza Houston, TX 77030; Department of Molecular and Human Genetics Baylor College of Medicine One Baylor Plaza Houston, TX 77030

* To whom correspondence should be addressed.
Jeffrey L. Noebels, E-mail: jnoebels{at}bcm.tmc.edu


  Abstract

Mutations in LGI1 have been linked to ADPEAF (autosomal dominant partial epilepsy, with auditory features), an unusual inherited human partial epilepsy phenotype. Furthermore, decreases in LGI1 expression are observed in glioblastoma patient samples and glioblastoma cell lines. LGI1, one member of the LGI gene family, encodes a ~63 kDa protein, with strong regional expression in neurons within the temporal lobe. While the function of LGI proteins remains unknown, structural analyses suggest that LGI1 could be either localized to the membrane or secreted. Here we show that LGI1-4 exhibit overlapping patterns of diffuse LGI family mRNA expression in the adult mouse brain with some areas of specific localization characteristic of each family member. We find robust secretion of mouse LGI1 protein following transfection into 293T cells. LGI family members, LGI3, LGI4, and a newly identified splice form of LGI2, LGI2B, are also secreted in culture indicating that secretion is a conserved feature of this protein family. Introduction of mutations in LGI1, including those identified in ADPEAF pedigrees, reveals that the mutant proteins are either not secreted or are unstable. These results demonstrate loss of function as a pathogenic basis for LGI1-mediated ADPEAF.


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