Alternative titles; symbols
HGNC Approved Gene Symbol: LGI1
SNOMEDCT: 784377008;
Cytogenetic location: 10q23.33 Genomic coordinates (GRCh38) : 10:93,757,936-93,798,159 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.33 | Epilepsy, familial temporal lobe, 1 | 600512 | Autosomal dominant | 3 |
The LGI1 gene encodes a secreted leucine-rich protein that is expressed in brain and plays a role in regulating postnatal glutamatergic synapse development (summary by Anderson, 2010).
Chernova et al. (1998) used a positional cloning strategy to isolate LGI1, which they found was rearranged as a result of a t(10;19)(q24;q13) balanced translocation in a glioblastoma (137800) cell line (T98G). The LGI1 cDNA predicts a precursor protein with 557 amino acids and a calculated molecular mass of 64 kD. After the cleavage of the signal peptide, the mature LGI1 protein is 60 kD. The protein contains a hydrophobic segment representing a putative transmembrane domain, with the amino terminus located outside the cell. It also contains 3.5 leucine-rich repeats (LRR) with conserved cysteine-rich flanking sequences. In the LRR domain, LGI1 shows high homology with a number of transmembrane and extracellular proteins that function as receptors and adhesion proteins. LGI1 is predominantly expressed in neural tissues, especially in brain; its expression is reduced in low-grade brain tumors and significantly reduced or absent in malignant gliomas.
Morante-Redolat et al. (2002) reported alternative splicing of exon 8, which appeared to vary between brain and skeletal muscle.
Most genes mutated in hereditary idiopathic epilepsies encode subunits of ion channels. Two apparent exceptions to this rule are the MASS1 gene (GPR98; 602851), which is mutated in the Frings mouse model of audiogenic epilepsy, and LGI1. Scheel et al. (2002) determined by amino acid analysis of both proteins that each contains a novel homology domain consisting of 7 repeats, each consisting of a 44-residue EAR (epilepsy-associated repeat) domain. The architecture and structural features of the EAR domain make it a likely member of the growing class of protein interaction domains with a 7-bladed beta-propeller fold. In the MASS1 gene product, which is a fragment of the very large G protein-coupled receptor VLGR1, the EAR domain is part of the ligand-binding ectodomain. LGI1, as well as a number of newly identified LGI1 relatives, is predicted to be a secreted protein, and consists of an N-terminal leucine-rich repeat region and a C-terminal EAR region. The human genome encodes at least 6 EAR proteins, some of which map to chromosomal regions associated with seizure disorders. Scheel et al. (2002) hypothesized that the EAR domain may play an important role in the pathogenesis of epilepsy, either by binding to an unknown antiepileptic ligand or by interfering with axon guidance or synaptogenesis.
Sirerol-Piquer et al. (2006) referred to the 7 tandem repeats of the LGI1 EAR domain as EPTP repeats. They reported that LGI1 also has 3 putative N-glycosylation sites.
Senechal et al. (2005) showed that Lgi1 was secreted in transfected 293T cells. In situ hybridization of adult mouse brain showed that Lgi1 mRNA is intensely expressed in granule cells of the dentate gyrus and the CA3-CA1 pyramidal cell layer of the hippocampus, with diffuse staining of the neocortex and other brain regions.
Nobile et al. (2009) noted that the LGI1 gene contains 8 exons spanning 39.6 kb.
Chernova et al. (1998) mapped the LGI1 gene to chromosome 10q24. Nobile et al. (2009) stated that the LGI1 gene maps to chromosome 10q23.33.
Chernova et al. (1998) found that the LGI1 gene was rearranged as a result of a t(10;19)(q24;q13) balanced translocation in a glioblastoma (137800) cell line (T98G). They suggested that the localization of LGI1 to the 10q24 region and its rearrangement or inactivation in malignant brain tumors make it a strong candidate tumor suppressor gene involved in the malignant progression of glial tumors. The study was performed because previous studies had found that loss of 1 copy of chromosome 10 is a common event in high-grade gliomas; rearrangement and loss of at least some parts of the second copy, especially in the 10q23-q26 region, had been demonstrated in approximately 80% of glioblastoma multiforme tumors (Bigner and Vogelstein, 1990). Chernova et al. (1998) also detected rearrangement of the LGI1 gene in the A172 glioblastoma cell line and several glioblastoma tumors, resulting in complete absence of LGI1 expression.
By semiquantitative PCR, Gu et al. (2002) detected expression of LGI1 in all tissues examined, with highest expression in brain. Immunolocalization revealed LGI1-immunoreactive neurons in all layers of the frontal and temporal cortex, with strongest labeling in layers II/III. Most of the labeled neurons displayed a pyramidal shape. Staining was detected within the perikaryon and occasionally in apical and basal dendrites, but not in nuclei. Similar labeling was found in all cortices investigated, but the intensities showed slight variations. The T98G glioblastoma cell line shows loss of LGI1 expression, and reexpression of LGI1 inhibits proliferation, invasiveness, and anchorage-independent growth.
Using gene expression arrays, Kunapuli et al. (2004) showed that forced reexpression of LGI1 in T98G cells resulted in downregulation of several metalloproteases, in particular MMP1 (120353) and MMP3 (185250). LGI1 expression also resulted in inhibition of ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948) phosphorylation, but not p38 (MAPK14; 600289) phosphorylation. Kunapuli et al. (2004) concluded that LGI1 plays a major role in suppressing production of metalloproteases through the ERK signaling pathway.
Gu et al. (2005) provided a detailed review of the LGI1 gene and concluded that the evidence supporting its role in malignant gliomas is weak.
Fukata et al. (2006) showed that ADAM22 (603709) serves as a receptor for LGI1. LGI1 enhances AMPA receptor-mediated synaptic transmission in hippocampal slices. The mutated form of LGI1 failed to bind to ADAM22. ADAM22 is anchored in the postsynaptic density by cytoskeletal scaffolds containing stargazin (602911). Fukata et al. (2006) found that the interaction of ADAM22 and LGI1 with PSD95 (602887) was specific, as PSD95 and LGI1 quantitatively coimmunoprecipitated with ADAM22. Because PSD95 controls synaptic AMPA receptor number, Fukata et al. (2006) asked whether application of LGI1 to hippocampal slices would influence glutaminergic transmission. Incubation of hippocampal slices in LGI1-AP media significantly increased the synaptic AMPA/NMDA ratio; nontagged LGI1 showed a similar effect. Fukata et al. (2006) concluded that their study established a neuronal ligand-receptor interaction between LGI1 and ADAM22, both of which are genetically related to epilepsy. This study also identified LGI1 as an extracellular factor that controls synaptic strength at the excitatory synapses. Stargazin controls the trafficking and gating of AMPA receptors,0j and PSD95 anchors the AMPA receptor/stargazin complex at postsynaptic sites. Because the ADAM22 and stargazin binding sites on PSD95 do not overlap, the LGI1/ADAM22 complex may stabilize the AMPA receptor/stargazin complex on the PSD95 scaffolding platform.
Using mutation analysis, Sirerol-Piquer et al. (2006) showed that the 3 putative N-glycosylation sites of human LGI1 were functional and that glycosylation was required for LGI1 secretion from transfected HEK293T cells. All 7 of the C-terminal EPTP repeats were also required for LGI1 secretion. LGI1 bound to the surface of neurally differentiated rat PC12 cells, and binding reduced the level of activated ERK1/ERK2.
Using immunostaining analysis, Hivert et al. (2019) showed that the voltage-gated Kv1 K+ channel (see 176260)-associated protein Lgi1 was targeted to the axon initial segment (AIS) of cultured rat hippocampal neurons. Lgi1 colocalized with Adam22, but not with Adam23 (603710). However, both ADAM proteins appeared to modulate Lgi1 targeting to the AIS. Coexpression analysis in HEK cells revealed that human ADAM22 and ADAM23 were involved in intracellular trafficking of LGI1 and promoted endoplasmic reticulum exit and N-glycan maturation of LGI1. Missense mutations in the EPTP6 domain of LGI1 reduced its interaction with ADAM22 and impaired its recruitment to the AIS. Moreover, Lgi1 and Adam23 colocalized in transport vesicles of rat hippocampal neurons, and Lgi1 likely required coexpression with Adam22 or Adam23 for proper trafficking and axonal transport.
Nobile et al. (2009) provided a review of the molecular genetics of the LGI1 gene, noting that 25 different pathogenic mutations had been identified. Most mutations are missense substitutions in both the N-terminal leucine-rich repeat (LRR) and C-terminal EPTP beta-propeller protein domains. No obvious genotype/phenotype correlations were observed.
By the positional candidate gene approach, Kalachikov et al. (2002) found that mutations in the LGI1 gene are responsible for autosomal dominant partial epilepsy with auditory features (ADLTE) (ETL1; 600512). The authors found 5 putative disease mutations in 5 families with this disorder (see, e.g., E383A; 604619.0001). They showed that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. It was not clear how homozygous loss of a predominantly neuronal gene produces results in glial tumor progression; however, such an effect was considered possible because neurons are known to inhibit glial mitosis, and interactions between neurons and glia appear to regulate homeostasis in both tissues.
Morante-Redolat et al. (2002) identified 2 truncating mutations (see, e.g., 604619.0005) in Spanish ADLTE families by direct sequencing. Since several other families with a phenotype consistent with this type of epilepsy lacked identifiable mutations in LGI1, the authors speculated that ADLTE may manifest genetic heterogeneity.
Sirerol-Piquer et al. (2006) found that all naturally occurring ADLTE-causing mutations in LGI1 that they examined, including both truncating and missense mutations, resulted in retention of LGI1 in the endoplasmic reticulum.
Chabrol et al. (2007) identified 2 respective mutations (604619.0008; L232P, 604619.0009) in a French and an Algerian family with ADLTE. By in vitro studies in Chinese hamster ovary (CHO) and rat adrenal pheochromocytoma cells, they demonstrated that wildtype LGI1 protein, but not E383A or L232P mutant protein, was secreted to the extracellular environment.
Fanciulli et al. (2012) identified a heterozygous 81-kb deletion encompassing part of the upstream region and the first 4 exons of the LGI1 gene (604619.0012) in affected members of a 3-generation Italian family with classic ADLTE. The deletion was found by CNV analysis after exon sequencing of the gene failed to identify a point mutation. The findings suggested that CNV analysis is a useful diagnostic tool for this disorder.
In an analysis of clinical and molecular information from the literature for all 36 published families with ADLTE due to an LGI1 mutation, Ho et al. (2012) found that pathogenic mutations clustered significantly more in the N-terminal LRR domains (exons 3-5) compared to the C-terminal EPTP domains (p = 0.026); however, mutations in both domains were clearly pathogenic. Auditory symptoms were less frequent in individuals with truncating mutations in the EPTP domain than in those with other mutation type/domain combinations (58% vs 80%, p = 0.018). The findings provided a basis for understanding the biologic pathways involved in ADLTE.
In rat brain, Schulte et al. (2006) found that Lgi1 stained prominently in the hippocampal formation, thalamic nuclei, and neocortex. In the hippocampus, Lgi1 was expressed in the outer and middle molecular layers of the dentate gyrus and was tightly associated with Kcna1 (176260)-containing channel complexes in presynaptic axon terminals. Functional studies showed that Lgi1 effectively and specifically prevented rapid voltage-gated potassium channel inactivation mediated by the Kv-beta-1 subunit (KCNAB1; 601141). In other words, Lgi1 effectively upregulates Kcna1 channels. Kcnab1 inactivation was not achieved with mutant Lgi1 proteins, and the loss of function showed a dominant effect in heterozygous coexpression studies with wildtype Lgi1. Schulte et al. (2006) suggested that mutations in LGI1 may lead to a complete loss of the Kcnab1-antagonizing effect of presynaptic potassium channels, resulting in increased channel activity and epileptogenesis.
In early postnatal wildtype mice, Zhou et al. (2009) found that expression of Lgi1 in hippocampus temporally coincided with maturation of presynaptic and postsynaptic functions. Presynaptic maturation was measured by a decrease in presynaptic release probability, whereas postsynaptic maturation was measured by functional changes in NMDA receptor NR2 subunit composition. In contrast, the normal postnatal maturation of presynaptic and postsynaptic function was arrested in a mouse model carrying an Lgi1 truncating mutation (835delC; 604619.0002), and was magnified in transgenic mice with overexpression of Lgi1. Zhou et al. (2009) postulated that Lgi1 acts normally at the presynaptic terminal to overcome KCNAB1-mediated KCNA1 presynaptic channel inhibition during postnatal development, perhaps before KCNAB1 is fully expressed, and lowers presynaptic release probability by upregulating presynaptic KCNA1 channel activity. Mutant truncated Lgi1 was also found to inhibit dendritic pruning, resulting in increased spine density and markedly increased excitatory synaptic transmission in mutant mice. Inhibitory transmission was unaffected. Mutant truncated Lgi1 promoted epileptiform discharge in vitro under partial GABAergic blockade, and caused kindling and decreased threshold for epileptogenesis in mutant mice in vivo, again under partial blockade of GABAergic blockade. Zhou et al. (2009) concluded that LGI1 regulates postnatal glutamatergic synapse development, and that mutant LGI1 acts as dominant-negative inhibitor to cause epilepsy.
Yu et al. (2010) reported that Lgi1-null mutant mice showed no gross overall developmental abnormalities on routine histopathologic analysis. After 12 to 18 days of age, the homozygous mutant mice all exhibited myoclonic seizures accompanied by rapid jumping and running, and died shortly thereafter. The heterozygous mutant mice did not develop seizures. Electrophysiologic analysis demonstrated an enhanced excitatory synaptic transmission by increasing the release of the excitatory neurotransmitter glutamate, suggesting a basis for the seizure phenotype.
In affected members of a family with autosomal dominant partial epilepsy with auditory features (ETL1; 600512), Kalachikov et al. (2002) identified a c.1372A-C transversion in exon 8 of the LGI1 gene, resulting in a missense glu383-to-ala (E383A) amino acid substitution in the fourth EAR domain.
Variant Function
By in vitro functional expression studies, Chabrol et al. (2007) demonstrated that the E383A mutant protein was not secreted into the culture medium, suggesting that a loss of function underlies pathogenesis of ADLTE.
In affected members of a family with autosomal dominant partial epilepsy with auditory features (ETL1; 600512), Kalachikov et al. (2002) found a 1-bp deletion, c.835delC, in exon 6 of the LGI1 gene.
Variant Function
By in vitro functional expression studies, Senechal et al. (2005) showed that the c.835delC-equivalent mutation in mouse Lgi1 resulted in decreased levels of secreted protein, indicating a loss-of-function mutation.
In affected members of a family with autosomal dominant partial epilepsy with auditory features (ETL1; 600512), Kalachikov et al. (2002) found a single nucleotide change, from C to A, at the third base from the acceptor intron-exon junction of exon 4. It was possible to show that a portion of the mRNA transcript had retention of the entire intron 3 as a result of the mutation.
In a large Norwegian family with autosomal dominant lateral temporal lobe epilepsy (ETL1; 600512) characterized by aphasic seizures, Gu et al. (2002) identified a cys46-to-arg substitution (C46R) in a conserved extracellular cysteine cluster region of the LGI1 gene. The authors noted that the conserved cysteine clusters likely form disulfide bonds important in a structural role of the protein. Mutation in the LGI1 gene may alter neuronal migration in the developing nervous system which would result in subtle lesions causing epilepsy.
In an Italian family with autosomal dominant partial epilepsy with auditory features, Pizzuti et al. (2003) identified a heterozygous change in the LGI1 gene, resulting in the C46R substitution.
In a 2-generation family with autosomal dominant lateral temporal lobe epilepsy (ETL1; 600512), Morante-Redolat et al. (2002) reported a c.1320C-T transition in exon 8 of LGI1 in affected family members. The mutation was predicted to generate a premature stop codon, eliminating the last 80 amino acids of the 557 amino-acid protein.
In a patient with sporadic ETL1, Bisulli et al. (2004) identified the c.1320C-T transition, which they termed c.1420C-T, as a de novo mutation. They suggested that the mutation was likely to be transmitted to the patient's offspring in an autosomal dominant pattern.
Fertig et al. (2003) reported a large American family of Italian descent with autosomal dominant partial epilepsy with auditory features (ETL1; 600512) with multiple affected members over 4 generations. Seven affected members and 1 unaffected member had a heterozygous c.953T-G transversion in exon 8 of the LGI1 gene, resulting in a phe318-to-cys (F318C) substitution. Mean age of onset was 25 years, and all patients reported an auditory aura preceding a secondary generalized seizure. The authors noted that the mutation occurred in the first EAR domain in the C terminus of the protein.
In a French father and daughter with autosomal dominant lateral temporal lobe epilepsy with auditory features (ETL1; 600512), Chabrol et al. (2007) identified a heterozygous G-to-A transition in intron 5 of the LGI1 gene (c.431+1G-A), resulting in the skipping of exons 3 and 4 and a protein predicted to lack 48 amino acids, suggesting a loss of function, although haploinsufficiency could not be ruled out. Two sibs of the daughter, 1 of whom was affected and 1 of whom may have been affected, had severe depression and committed suicide. The daughter also had severe depression.
In 3 members of an Algerian family with autosomal dominant lateral temporal lobe epilepsy with auditory features (ETL1; 600512), Chabrol et al. (2007) identified a heterozygous c.695T-C transition in exon 7 of the LGI1 gene, resulting in a leu232-to-pro (L232P) substitution in the second EAR domain. In vitro functional expression studies showed that the L232P mutant protein was not secreted into the culture medium, suggesting a loss of function underlies the pathogenesis of ADLTE.
In a 36-year-old woman with lateral temporal lobe epilepsy (ETL1; 600512) manifest as telephone-induced seizures, Michelucci et al. (2007) identified a de novo heterozygous c.406C-T transition in exon 4, resulting in an arg136-to-trp (R136W) substitution. The patient had an 11-year history of recurrent partial complex and secondarily generalized seizures evoked almost exclusively by answering the telephone. Other auditory stimuli could also elicit seizures. The seizures were accompanied by distortion or attenuation of sound, inability to understand language, and inability to speak appropriately, all consistent with lateral temporal lobe involvement.
In affected members of a Italian family with autosomal dominant lateral temporal lobe epilepsy (ETL1; 600512), Striano et al. (2008) identified a heterozygous c.365T-A transversion in exon 4 of the LGI1 gene, resulting in an ile122-to-lys (I122K) substitution in a highly conserved residue. The affected residue is part of the hydrophobic core of the second leucine-rich repeat and is important for proper protein folding. In vitro functional expression studies in cultured HEK293 cells followed by western blot analysis showed that the mutant protein was translated but not secreted. Striano et al. (2008) noted that the findings were consistent with LGI1 functioning as an extracellular ligand.
In affected members of a 3-generation Italian family with autosomal dominant lateral temporal lobe epilepsy (ETL1; 600512), Fanciulli et al. (2012) identified a heterozygous 81-kb deletion encompassing part of the upstream region and the first 4 exons of the LGI1 gene, predicted to result in a loss of function. The deletion was found by CNV analysis after exon sequencing of the gene failed to identify a point mutation. The deletion was not found in several large databases. There were 8 affected individuals. Most patients had onset of seizures in the second decade, although 2 had onset as adults. Six had tonic-clonic seizures with focal onset, and most experienced accompanying auditory features. Brain imaging was unremarkable in all patients who were studied, and EEG showed mild abnormalities only in 3 patients. Patients showed a good response to antiepileptic medication. Two unaffected family members, aged 24 and 17 years, also carried the deletion, consistent with later onset of the disorder or incomplete penetrance.
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