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 approximately 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.