Details for: LGI3

Gene ID: 203190

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: LGI3

Ensembl ID: ENSG00000168481

Description: leucine rich repeat LGI family member 3

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • inhibitory interneuron CL0000498
    CSI 3.04
    rCSI 7.01%
    PRS 94.04
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 2.58
    rCSI 8.06%
    PRS 94.5
  • pulmonary alveolar type 2 cell CL0002063
    CSI 2.52
    rCSI 3.91%
    PRS 97.78
  • cerebral cortex neuron CL0010012
    CSI 2.07
    rCSI 8.43%
    PRS 93.63
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 2.04
    rCSI 2.53%
    PRS 92.27
  • retinal ganglion cell CL0000740
    CSI 1.63
    rCSI 3.59%
    PRS 93.41
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 1.43
    rCSI 5.16%
    PRS 92.38
  • dopaminergic neuron CL0000700
    CSI 1.26
    rCSI 7.14%
    PRS 92.64
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.23
    rCSI 2.98%
    PRS 92.15
  • L6b glutamatergic cortical neuron CL4023038
    CSI 0.87
    rCSI 2.73%
    PRS 93.9

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
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    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [LGI3](/details-gene/203190) (leucine rich repeat LGI family member 3) is a protein-coding gene located on chromosome 8p21.3. As a member of the LGI family, which is implicated in certain forms of epilepsy ([Link](https://doi.org/10.1016/s0014-5793(02)02713-8)), [LGI3](/details-gene/203190) encodes a secreted protein that plays a role in the regulation of exocytosis. Functional annotations place it in the extracellular space and associate it with synaptic vesicles and the juxtaparanode region of axons. **Overall**, expression data reveals that [LGI3](/details-gene/203190) is a significant marker for various neuronal subtypes, particularly [inhibitory interneurons](/details-cell/CL0000498) and [chandelier pvalb GABAergic cortical interneurons](/details-cell/CL4023036), suggesting a specialized role in the central nervous system. ## Cellular Roles and Expression Landscape The expression profile of [LGI3](/details-gene/203190) strongly indicates a primary function within the nervous system. **Overall**, it demonstrates the highest significance in neuronal populations, particularly those involved in inhibitory signaling. It is a top marker for [inhibitory interneurons](/details-cell/CL0000498) (CSI: 3.04) and more specific subtypes such as [chandelier pvalb GABAergic cortical interneurons](/details-cell/CL4023036) (CSI: 2.58) and [pvalb GABAergic cortical interneurons](/details-cell/CL4023018) (CSI: 2.04). Beyond inhibitory cells, [LGI3](/details-gene/203190) is also significantly expressed in various excitatory and specialized neurons, including [cerebral cortex neurons](/details-cell/CL0010012) (CSI: 2.07), [L5 extratelencephalic projecting glutamatergic cortical neurons](/details-cell/CL4023041) (CSI: 1.43), [retinal ganglion cells](/details-cell/CL0000740) (CSI: 1.63), and [dopaminergic neurons](/details-cell/CL0000700) (CSI: 1.26). This broad but neuron-centric expression pattern suggests a fundamental role in regulating neuronal communication across different circuits. Interestingly, [LGI3](/details-gene/203190) also shows high significance in a non-neuronal cell type, the [pulmonary alveolar type 2 cell](/details-cell/CL0002063) (CSI: 2.52). These cells are responsible for secreting pulmonary surfactant via exocytosis, which aligns with the known molecular function of [LGI3](/details-gene/203190) and suggests a conserved role in regulating secretory processes outside the nervous system. ## Pathways and Molecular Function Functionally, [LGI3](/details-gene/203190) is annotated as an extracellular protein ([GO:0005576](https://www.ebi.ac.uk/QuickGO/term/GO:0005576)) involved in [Exocytosis](/details-pathway/GO:0006887) and its regulation ([GO:0017157](https://www.ebi.ac.uk/QuickGO/term/GO:0017157)). Its localization to the [juxtaparanode region of the axon](/details-pathway/GO:0044224) and [synaptic vesicles](/details-pathway/GO:0008021) is consistent with its high expression in neurons and points towards a function in modulating neurotransmitter release and maintaining synaptic integrity. The Reactome pathway analysis highlights its involvement in [Lgi-adam interactions](/details-pathway/R-HSA-5682910), a mechanism shared by other LGI family members where they interact with ADAM (A Disintegrin and Metalloproteinase) proteins. These interactions are critical for synaptic function and development, and their disruption by LGI1 mutations is a known cause of epilepsy ([Link](https://doi.org/10.1093/hmg/11.15.1757)). This suggests that [LGI3](/details-gene/203190) likely functions by modulating the activity of cell surface receptors or adhesion molecules through its interaction with ADAM proteases, thereby influencing cell-cell communication. ## Research Directions The specific expression pattern and molecular function of [LGI3](/details-gene/203190) suggest several avenues for future investigation, particularly concerning its role in neuronal circuit function and non-neuronal secretory processes. **Proposed Hypotheses:** 1. Given its high significance in GABAergic interneurons and its role in regulating exocytosis, dysregulation or loss of [LGI3](/details-gene/203190) function may lead to impaired inhibitory neurotransmission, contributing to an excitation/inhibition imbalance that could lower the threshold for seizures, consistent with the broader role of the LGI family in epilepsy. 2. The high significance of [LGI3](/details-gene/203190) in [pulmonary alveolar type 2 cells](/details-cell/CL0002063) suggests it plays a critical, non-neuronal role in the lung by regulating the exocytosis of surfactant-containing lamellar bodies, potentially impacting lung function and response to injury. **Experimental Approach:** To test the hypothesis regarding its role in inhibitory neurotransmission, a compelling experiment would be to generate a conditional knockout mouse model where `Lgi3` is specifically deleted in Pvalb-expressing interneurons. Using slice electrophysiology, one could perform whole-cell patch-clamp recordings from postsynaptic pyramidal neurons to measure inhibitory postsynaptic currents (IPSCs). A reduction in the frequency or amplitude of spontaneous or evoked IPSCs in the knockout mice compared to wild-type controls would provide direct evidence for [LGI3](/details-gene/203190)'s role in maintaining GABAergic synaptic function. **Therapeutic Potential:** As a secreted, extracellular protein, [LGI3](/details-gene/203190) is a potentially accessible drug target. If loss-of-function mutations are linked to neurological disorders like epilepsy, a protein-replacement therapy using recombinant [LGI3](/details-gene/203190) or a small molecule designed to enhance its interaction with its binding partners (e.g., ADAM proteins) could be a viable strategy for activation. Conversely, if its overexpression or aberrant activity contributes to pathology, it could be targeted for inhibition using neutralizing antibodies or small molecules that block its protein-protein interactions. Its specificity for neuronal circuits suggests that modulating its function could offer a targeted approach for treating disorders of neuronal hyperexcitability.

Genular Protein ID: 3095627293

Symbol: LGI3_HUMAN

Name: Leucine-rich repeat LGI family member 3

UniProtKB Accession Codes:

Q8N145 A5PLP2 Q86TL4 Q8N296

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 8 Ensembl 2 ExpressionAtlas 1 GO 6 Gene3D 1 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 8 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 1 RefSeq 1 SMART 2 SMR 1 STRING 1 SUPFAM 2 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 12023020

Title: The LGI1 gene involved in lateral temporal lobe epilepsy belongs to a new subfamily of leucine-rich repeat proteins.

PubMed ID: 12023020

DOI: 10.1016/s0014-5793(02)02713-8

PubMed ID: 12095917

Title: A common protein interaction domain links two recently identified epilepsy genes.

PubMed ID: 12095917

DOI: 10.1093/hmg/11.15.1757

PubMed ID: 12217514

Title: The novel EPTP repeat defines a superfamily of proteins implicated in epileptic disorders.

PubMed ID: 12217514

DOI: 10.1016/s0968-0004(02)02163-1

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16421571

Title: DNA sequence and analysis of human chromosome 8.

PubMed ID: 16421571

DOI: 10.1038/nature04406

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 35948005

Title: A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.

PubMed ID: 35948005

DOI: 10.1016/j.ajhg.2022.07.006

Sequence Information:

  • Length: 548
  • Mass: 61704
  • Checksum: 32FE6EABA184E47B
  • Sequence:
    • MAGLRARGGP GPGLLALSAL GFCLMLQVSA KRPPKTPPCP PSCSCTRDTA FCVDSKAVPR 
NLPSEVISLT LVNAAFSEIQ DGAFSHLPLL QFLLLNSNKF TLIGDNAFTG LSHLQYLFIE 
NNDIWALSKF TFRGLKSLTH LSLANNNLQT LPRDIFRPLD ILNDLDLRGN SLNCDCKVKW 
LVEWLAHTNT TVAPIYCASP PRFQEHKVQD LPLREFDCIT TDFVLYQTLA FPAVSAEPFL 
YSSDLYLALA QPGVSACTIL KWDYVERQLR DYDRIPAPSA VHCKPMVVDS QLYVVVAQLF 
GGSYIYHWDP NTTRFTRLQD IDPQRVRKPN DLEAFRIDGD WYFAVADSSK AGATSLYRWH 
QNGFYSHQAL HPWHRDTDLE FVDGEGKPRL IVSSSSQAPV IYQWSRTQKQ FVAQGEVTQV 
PDAQAVKHFR AGRDSYLCLS RYIGDSKILR WEGTRFSEVQ ALPSRGSLAL QPFLVGGRRY 
LALGSDFSFT QIYQWDEGRQ KFVRFQELAV QAPRAFCYMP AGDAQLLLAP SFKGQTLVYR 
HIVVDLSA