LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology

Owuor, Katherine; Harel, Noam Y.; Englot, Dario J.; Hisama, Fuki M.; Blumenfeld, Hal; Strittmatter, Stephen M.

doi:10.1016/j.mcn.2009.09.008

Cited by 90 publications

(95 citation statements)

References 30 publications

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“…PSD-95, which directly interacts with one major ADAM22 isoform with a PDZ-binding motif (8), was also coimmunoprecipitated with ADAM22 and ADAM23 in wild-type mouse brain. A recent study revealed that ADAM23 mRNA does not express in granule cells of the hippocampal dentate gyrus (12). Our immunohistochemical analysis showed that ADAM23 protein localizes in the outer molecular layers of the dentate gyrus (Fig.…”

Section: Resultsmentioning

confidence: 57%

“…Consistently, LGI1 directly bound to both ADAM22 and ADAM23 in vitro ( Fig. S2A) (8,12,13). Furthermore, to identify overall constituents of the LGI1 complex including indirect interactions, we conducted large-scale purification combined with shotgun proteomic analysis.…”

Section: Resultsmentioning

confidence: 71%

“…Also identified was 14-3-3, a known binding partner of ADAM22 (14). Interestingly, each targeted disruption of ADAM22 (11), ADAM23 (12,15), and Kv 1 channel (Kv 1.1 (16) and Kv 1.2 (17), which form heterotetramer in the brain) causes a similar epileptic phenotype (generalized tonic-clonic seizures beginning around the postnatal second or third week) and premature death in mice, suggesting that LGI1, ADAM22, ADAM23, and Kv 1 channel are genetically associated and functionally related.…”

Section: Resultsmentioning

confidence: 99%

“…Phenotypes of LGI1 gene-targeted mice, increased seizure susceptibility in heterozygous LGI1 +/− mice and lethal epileptic seizures in homozygous LGI1 −/− mice provide supportive evidence for the haploinsufficiency mechanism of ADPEAF mutations in human; ADPEAF mutations perturb LGI1 secretion and reduce the LGI1-mediated transsynaptic connection between ADAM22 and ADAM23, leading to abnormal synaptic transmission and epilepsy. Because heterozygous mice for ADAM23 gene disruption show the similar susceptibility to PTZ (12), and homozygous mice for ADAM22 or ADAM23 mutation show spontaneous lethal seizures (11,12,15), it is strongly suggested that the amount of LGI1/ADAM22/ADAM23 complex determines seizure susceptibility. One may ask about the relationship between the phenotype of heterozygous LGI1 +/− mice and the clinical features of ADPEAF patients.…”

Section: Discussionmentioning

confidence: 99%

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Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy

Fukata¹,

Lovero

Iwanaga³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

299

392

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Epilepsy is a devastating and poorly understood disease. Mutations in a secreted neuronal protein, leucine-rich glioma inactivated 1 (LGI1), were reported in patients with an inherited form of human epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF). Here, we report an essential role of LGI1 as an antiepileptogenic ligand. We find that loss of LGI1 in mice (LGI1 −/− ) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3. Moreover, heterozygous mice for the LGI1 mutation (LGI1 +/− ) show lowered seizure thresholds. Extracellularly secreted LGI1 links two epilepsy-related receptors, ADAM22 and ADAM23, in the brain and organizes a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus. Thus, LGI1 may serve as a major determinant of brain excitation, and the LGI1 gene-targeted mouse provides a good model for human epilepsy.A ffecting 1-2% of the population, epilepsy is one of the most common neurological disorders. Epilepsy is characterized by recurrent unprovoked seizures and is caused by disturbances in the delicate balance between excitation and inhibition in neural circuits (1, 2). Recent human genetic studies have established the channelopathy concept for idiopathic (inherited) epilepsies: Many of the genes whose mutations cause human epilepsy encode ion channel subunits (1, 2). Examples include voltagegated ion channels (K + , Na + , Ca 2+ , and Cl -channels) and ligandgated ion channels (nicotinic acetylcholine and GABA A receptors), which regulate neuronal excitability.Leucine-rich glioma inactivated 1 (LGI1) is a unique human epilepsy-related gene in that it does not encode an ion channel subunit (3-5), but is a neuronal secreted protein (6). Mutations in LGI1 are linked to autosomal dominant partial epilepsy with auditory features (ADPEAF, also known as autosomal dominant lateral temporal lobe epilepsy [ADLTE]) (3-5), which is an inherited epileptic syndrome characterized by partial seizures with acoustic or visual hallucinations. So far, 25 LGI1 mutations have been described in familial ADPEAF patients and sporadic cases (7). Interestingly, at least six tested ADPEAF mutations all abolish LGI1 secretion (6,8).Recent proteomic analysis identified LGI1 as a subunit of presynaptic Kv 1 (shaker type)-voltage gated potassium channels (9). It was shown that LGI1 selectively prevents inactivation of the Kv 1 channel mediated by a cytoplasmic regulatory protein, Kvβ. Because LGI1 is a secreted protein, it remains unclear how LGI1 modulates a cytosolic potassium channel mechanism. LGI1 was also isolated from the brain as a component of a protein complex mediated by PSD-95, a representative postsynaptic scaffolding protein.LGI1 functions as a ligand for the epilepsy-related ADAM22 transmembrane protein, which is anchored by PS...

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Section: Resultsmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy

Fukata¹,

Lovero

Iwanaga³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

299

392

View full text Add to dashboard Cite

show abstract

“…LGI1 mutations cause ADTLE in humans and recent studies have shown that the interaction of LGI1 with ADAM22 has profound effects on synaptic transmission and dendritic maturation (Owuor et al, 2009;Zhou et al, 2009). Interestingly, analysis of NgR1 nulls has revealed that NgR1 also functions at central synapses (McGee et al, 2005;Lee et al, 2008).…”

Section: Ngr1 and Adam22 Associate To Form An Lgi1 Binding Complexmentioning

confidence: 99%

LGI1 Is a Nogo Receptor 1 Ligand that Antagonizes Myelin-Based Growth Inhibition

Thomas

Favell²,

Morante‐Redolat³

et al. 2010

J. Neurosci.

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Mutations in leucine-rich glioma inactivated (LGI1) are a genetic cause of autosomal dominant temporal lobe epilepsy with auditory features.LGI1 is a secreted protein that shares homology with members of the SLIT family, ligands that direct axonal repulsion and growth cone collapse, and we therefore considered the possibility that LGI1 may regulate neuronal process extension or growth cone collapse. Here we report that LGI1 does not affect growth directly but instead enhances neuronal growth on myelin-based inhibitory substrates and antagonizes myelin-induced growth cone collapse. We show that LGI1 mediates this effect by functioning as a specific Nogo receptor 1 (NgR1) ligand that antagonizes the action of myelin-based inhibitory cues. Finally, we demonstrate that NgR1 and ADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22.

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Rare copy number variants are an important cause of epileptic encephalopathies

Mefford¹,

Yendle²,

Hsu³

et al. 2011

Annals of Neurology

227

183

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Objective Rare copy number variants (CNVs) – deletions and duplications – have recently been established as important risk factors for both generalized and focal epilepsies. A systematic assessment of the role of CNVs in epileptic encephalopathies, the most devastating and often etiologically obscure, group of epilepsies, has not been performed. Methods We evaluated 315 patients with epileptic encephalopathies characterized by epilepsy and progressive cognitive impairment for rare CNVs using a high-density, exon-focused whole-genome oligonucleotide array. Results We found that 25/315 (7.9%) of our patients carried rare CNVs that may contribute to their phenotype, with at least half being clearly or likely pathogenic. We identified two patients with overlapping deletions at 7q21 and two patients with identical duplications of 16p11.2. In our cohort, large deletions were enriched in affected individuals compared to controls, and four patients harbored two rare CNVs. We screened two novel candidate genes found within the rare CNVs in our cohort but found no mutations in our patients with epileptic encephalopathies. We highlight several additional novel candidate genes located in CNV regions. Interpretation Our data highlight the significance of rare copy number variants in the epileptic encephalopathies, and we suggest that CNV analysis should be considered in the genetic evaluation of these patients. Our findings also highlight novel candidate genes for further study.

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LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology

Cited by 90 publications

References 30 publications

Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy

Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy

LGI1 Is a Nogo Receptor 1 Ligand that Antagonizes Myelin-Based Growth Inhibition

Rare copy number variants are an important cause of epileptic encephalopathies

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