Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Hum Mol Genet 2006 Dec 01
PMID:The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface. 1706 99

Most epilepsy genes encode ion channels, but the LGI1 gene responsible for autosomal dominant partial epilepsy with auditory features produces a secreted protein. LGI1 is suggested to regulate PSD-95 via ADAM22. However, no unbiased screen of LGI1 action has been conducted. Here, we searched for brain genes supporting high affinity LGI-1 binding. ADAM23 was the only LGI1 interactor identified. The related proteins, ADAM22 and ADAM11, but not ADAM12, bind LGI1. Neither ADAM23 nor ADAM11, nor some forms of ADAM22, contain PDZ-interacting sequences, suggesting PSD-95-independent mechanisms in ADPEAF. Because ADAMs modulate integrins, we examined LGI1 effect on neurite outgrowth. LGI1 increases outgrowth from wild-type but not ADAM23-/- neurons. Furthermore, CA1 pyramidal neurons of ADAM23-/- hippocampi have reduced dendritic arborization. ADAM23-/- mice exhibit spontaneous seizures, while ADAM23+/- mice have decreased seizure thresholds. Thus, LGI1 binding to ADAM23 is necessary to correctly pattern neuronal morphology and altered anatomical patterning contributes to ADPEAF.
Mol Cell Neurosci 2009 Dec
PMID:LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology. 1979 86

Epilepsy is one of the most common brain disorders, which can be caused by abnormal synaptic transmissions. Many epilepsy-related mutations have been identified in synaptic ion channels, which are main targets for current antiepileptic drugs. One of the novel potential targets for therapy of epilepsy is a class of non-ion channel-type epilepsy-related proteins. The leucine-rich repeat glioma-inactivated protein 1 (LGI1) is a neuronal secreted protein, and has been extensively studied as a product of a causative gene for autosomal dominant lateral temporal lobe epilepsy (ADLTE; also known as autosomal dominant partial epilepsy with auditory features [ADPEAF]). At least 43 mutations of LGI1 have been found in ADLTE families. Additionally, autoantibodies against LGI1 in limbic encephalitis are associated with amnesia, seizures, and cognitive dysfunction. Although the relationship of LGI1 with synaptic transmission and synaptic disorders has been studied genetically, biochemically, and clinically, the structural mechanism of LGI1 remained largely unknown until recently. In this review, we introduce insights into pathogenic mechanisms of LGI1 from recent structural studies on LGI1 and its receptor, ADAM22. We also discuss the mechanism for pathogenesis of autoantibodies against LGI1, and the potential of chemical correctors as novel drugs for epilepsy, with structural aspects of LGI1-ADAM22.
Cell Mol Life Sci 2020 Jan
PMID:Insights into the mechanisms of epilepsy from structural biology of LGI1-ADAM22. 3143 33