ADPEAF mutations reduce levels of secreted LGI1, a putative tumor suppressor protein linked to epilepsy
Open Access
- 27 April 2005
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 14 (12), 1613-1620
- https://doi.org/10.1093/hmg/ddi169
Abstract
Mutations in LGI1 have been linked to autosomal dominant partial epilepsy with auditory features (ADPEAF), an unusual inherited human partial epilepsy phenotype. In addition, 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. Although 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 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 either are not secreted or are unstable. These results demonstrate loss-of-function as a pathogenic basis for LGI1-mediated ADPEAF.Keywords
This publication has 25 references indexed in Scilit:
- Comprehensive expression atlas of fibroblast growth factors and their receptors generated by a novel robotic in situ hybridization platformDevelopmental Dynamics, 2005
- LGI1, a Putative Tumor Metastasis Suppressor Gene, Controls in Vitro Invasiveness and Expression of Matrix Metalloproteinases in Glioma Cells through the ERK1/2 PathwayPublished by Elsevier BV ,2004
- Autosomal Dominant Lateral Temporal Epilepsy: Two Families with Novel Mutations in the LGI1 GeneEpilepsia, 2004
- Autosomal Dominant Lateral Temporal Epilepsy: Clinical Spectrum, New Epitempin Mutations, and Genetic Heterogeneity in Seven European FamiliesEpilepsia, 2003
- Suppression of the cell proliferation and invasion phenotypes in glioma cells by the LGI1 geneOncogene, 2003
- Epilepsy with auditory features: A LGI1 gene mutation suggests a loss‐of‐function mechanismAnnals of Neurology, 2003
- LGI1 is mutated in familial temporal lobe epilepsy characterized by aphasic seizuresAnnals of Neurology, 2002
- Role of Rapsyn Tetratricopeptide Repeat and Coiled-coil Domains in Self-association and Nicotinic Acetylcholine Receptor ClusteringPublished by Elsevier BV ,2001
- A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumorsOncogene, 1998
- Localization of a gene for partial epilepsy to chromosome 10qNature Genetics, 1995