Details for: LHX3

Gene ID: 8022

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: LHX3

Ensembl ID: ENSG00000107187

Description: LIM homeobox 3

Cell Significance Landscape

Associated with

Significant Cells

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

  • OFF-bipolar cell CL0000750
    CSI 4.35
    rCSI 5.95%
    PRS 99.97

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

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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 [LHX3](/details-gene/8022) (LIM Homeobox 3) is a protein-coding gene located on chromosome 9q34.3. It encodes a transcription factor belonging to the LIM-homeodomain family, which is characterized by the presence of two N-terminal LIM domains and a C-terminal DNA-binding homeodomain. As a sequence-specific DNA-binding transcription factor, [LHX3](/details-gene/8022) plays a fundamental role in embryonic development, particularly in the morphogenesis of the pituitary gland and the central nervous system. Its function is critical for the differentiation of multiple anterior pituitary cell lineages and for motor neuron specification and axon guidance. Mutations in [LHX3](/details-gene/8022) are associated with combined pituitary hormone deficiency (CPHD), a clinical syndrome that can include severe growth retardation, hormonal imbalances, and neurological defects such as limited neck rotation and hearing loss ([600577](https://omim.org/entry/600577), [221750](https://omim.org/entry/221750)). ## Cellular Roles and Expression Landscape The expression profile of [LHX3](/details-gene/8022) points to a highly specialized role in specific neuronal and endocrine cell types. **Overall**, the most significant expression for [LHX3](/details-gene/8022) is observed in [OFF-bipolar cells](/details-cell/CL0000750) (CSI: 4.35), a type of retinal interneuron. This finding is supported by studies identifying its expression in human retinal cell lines ([Link](https://doi.org/10.1167/iovs.11-7479)), suggesting a role in the development or function of the visual system. While direct expression data is limited to this cell type, functional annotations strongly imply its importance in other specialized cells. Gene Ontology terms indicate a critical function in the differentiation of multiple pituitary hormone-secreting cells, including [somatotropin secreting cells](/details-go/GO:0060126), [prolactin secreting cells](/details-go/GO:0060127), and [thyroid-stimulating hormone-secreting cells](/details-go/GO:0060129). This is consistent with extensive clinical evidence linking [LHX3](/details-gene/8022) mutations to CPHD ([Link](https://doi.org/10.1038/76041)). Furthermore, its established role in nervous system development suggests significant activity in [medial motor column neuron differentiation](/details-go/GO:0021526) and [spinal cord association neuron differentiation](/details-go/GO:0021527) during embryogenesis. ## Pathways and Molecular Function [LHX3](/details-gene/8022) functions primarily as a DNA-binding transcription activator located in the [nucleus](/details-go/GO:0005634), where it forms part of [transcription regulator complexes](/details-go/GO:0005667). Its molecular activity centers on [RNA polymerase II cis-regulatory region sequence-specific DNA binding](/details-go/GO:0000978), enabling it to positively regulate the transcription of target genes ([GO:0045893](https://www.ebi.ac.uk/QuickGO/term/GO:0045893)). The biological processes governed by [LHX3](/details-gene/8022) are central to the [Developmental Biology](/details-reactome/R-HSA-1266738) super-pathway. Key annotated pathways include [Nervous system development](/details-reactome/R-HSA-9675108) and [Axon guidance](/details-reactome/R-HSA-422475). Its involvement in these pathways is critical for establishing correct neuronal circuitry during embryonic development. Studies have demonstrated that different isoforms of [LHX3](/details-gene/8022) possess distinct DNA-binding properties, allowing for differential activation of pituitary hormone genes ([Link](https://doi.org/10.1210/mend.13.12.0395)). The loss of its function disrupts these developmental programs, leading to the severe endocrine and neurological phenotypes seen in patients ([Link](https://doi.org/10.1073/pnas.1009501108)). ## Research Directions The established role of [LHX3](/details-gene/8022) in congenital disorders provides a clear basis for further investigation into its precise molecular mechanisms and potential therapeutic avenues. Mutations in the gene are known to cause a syndrome of combined pituitary hormone deficiencies, often accompanied by cervical rigidity and sensorineural hearing loss, highlighting its pleiotropic effects ([Link](https://doi.org/10.1186/s12902-017-0164-8)). Based on the available data, several testable hypotheses can be proposed: 1. Given its high significance in [OFF-bipolar cells](/details-cell/CL0000750) and its general role in neuron differentiation ([GO:0030182](https://www.ebi.ac.uk/QuickGO/term/GO:0030182)), [LHX3](/details-gene/8022) is likely indispensable for the lineage specification or synaptic integration of this specific class of retinal interneurons. 2. The clinical association with sensorineural hearing loss and the annotated function in [inner ear development](/details-go/GO:0048839) suggest that [LHX3](/details-gene/8022) regulates a specific transcriptional program required for the differentiation or survival of auditory hair cells or their associated spiral ganglion neurons. To test the first hypothesis regarding its role in retinal development, a key experiment would be to use CRISPR-Cas9 to generate a knockout of [LHX3](/details-gene/8022) in human induced pluripotent stem cells (iPSCs). These iPSCs could then be differentiated into retinal organoids. A combination of single-cell RNA sequencing and immunofluorescence for bipolar cell markers (e.g., OTX2, GRIK1) would be used to determine if the loss of [LHX3](/details-gene/8022) leads to a specific deficit in the generation or maturation of [OFF-bipolar cells](/details-cell/CL0000750) compared to control organoids. As a therapeutic target, [LHX3](/details-gene/8022) is not a candidate for inhibition, as its pathology stems from loss-of-function mutations. The therapeutic potential would lie in gene augmentation or replacement strategies for affected individuals. However, its role as a master developmental transcription factor presents significant challenges, as its precise temporal and spatial expression is critical. Ectopic or improperly timed expression could have severe unintended consequences, making therapeutic applications complex and requiring sophisticated delivery and regulation systems.

Genular Protein ID: 3172669007

Symbol: LHX3_HUMAN

Name: LIM/homeobox protein Lhx3

UniProtKB Accession Codes:

Q9UBR4 Q5TB39 Q5TB40 Q9NZB5 Q9P0I8 Q9P0I9

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 3 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 13 Ensembl 2 ExpressionAtlas 1 GO 29 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 7 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 2 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 4 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 RNAct 1 Reactome 1 RefSeq 2 SIGNOR 1 SMART 2 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 10598593

Title: Differential activation of pituitary hormone genes by human Lhx3 isoforms with distinct DNA binding properties.

PubMed ID: 10598593

DOI: 10.1210/mend.13.12.0395

PubMed ID: 15164053

Title: DNA sequence and analysis of human chromosome 9.

PubMed ID: 15164053

DOI: 10.1038/nature02465

PubMed ID: 15517599

Title: Serine/threonine/tyrosine phosphorylation of the LHX3 LIM-homeodomain transcription factor.

PubMed ID: 15517599

DOI: 10.1002/jcb.20287

PubMed ID: 21149718

Title: Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo.

PubMed ID: 21149718

DOI: 10.1073/pnas.1009501108

PubMed ID: 26612202

Title: Functional characterization of a human POU1F1 mutation associated with isolated growth hormone deficiency: a novel etiology for IGHD.

PubMed ID: 26612202

DOI: 10.1093/hmg/ddv486

PubMed ID: 10835633

Title: Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency.

PubMed ID: 10835633

DOI: 10.1038/76041

PubMed ID: 17327381

Title: Four novel mutations of the LHX3 gene cause combined pituitary hormone deficiencies with or without limited neck rotation.

PubMed ID: 17327381

DOI: 10.1210/jc.2006-2177

PubMed ID: 28302169

Title: Two novel LHX3 mutations in patients with combined pituitary hormone deficiency including cervical rigidity and sensorineural hearing loss.

PubMed ID: 28302169

DOI: 10.1186/s12902-017-0164-8

Sequence Information:

  • Length: 397
  • Mass: 43358
  • Checksum: FB4A2E48C015C249
  • Sequence:
    • MLLETGLERD RARPGAAAVC TLGGTREIPL CAGCDQHILD RFILKALDRH WHSKCLKCSD 
CHTPLAERCF SRGESVYCKD DFFKRFGTKC AACQLGIPPT QVVRRAQDFV YHLHCFACVV 
CKRQLATGDE FYLMEDSRLV CKADYETAKQ REAEATAKRP RTTITAKQLE TLKSAYNTSP 
KPARHVREQL SSETGLDMRV VQVWFQNRRA KEKRLKKDAG RQRWGQYFRN MKRSRGGSKS 
DKDSVQEGQD SDAEVSFPDE PSLAEMGPAN GLYGSLGEPT QALGRPSGAL GNFSLEHGGL 
AGPEQYRELR PGSPYGVPPS PAAPQSLPGP QPLLSSLVYP DTSLGLVPSG APGGPPPMRV 
LAGNGPSSDL STGSSGGYPD FPASPASWLD EVDHAQF

Genular Protein ID: 314537252

Symbol: F1T0D9_HUMAN

Name: N/A

UniProtKB Accession Codes:

F1T0D9

Database IDs:

ARBA 12 AlphaFoldDB 1 Antibodypedia 1 BioGRID-ORCS 1 CDD 3 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 2 ExpressionAtlas 1 GO 5 Gene3D 2 InterPro 7 NCBI Taxonomy 1 OMA 1 OrthoDB 1 PANTHER 2 PROSITE 6 PROSITE-ProRule 2 Pfam 2 PhylomeDB 1 RefSeq 1 RuleBase 1 SAM 1 SMART 2 SMR 1 SUPFAM 2 VEuPathDB 1

Citations:

PubMed ID: 21697133

Title: Full-length transcriptome analysis of human retina-derived cell lines ARPE-19 and Y79 using the vector-capping method.

PubMed ID: 21697133

DOI: 10.1167/iovs.11-7479

Sequence Information:

  • Length: 402
  • Mass: 43978
  • Checksum: 23B71558AC877672
  • Sequence:
    • MEARGELGPA RESAGGDLLL ALLARRADLR REIPLCAGCD QHILDRFILK ALDRHWHSKC 
LKCSDCHTPL AERCFSRGES VYCKDDFFKR FGTKCAACQL GIPPTQVVRR AQDFVYHLHC 
FACVVCKRQL ATGDEFYLME DSRLVCKADY ETAKQREAEA TAKRPRTTIT AKQLETLKSA 
YNTSPKPARH VREQLSSETG LDMRVVQVWF QNRRAKEKRL KKDAGRQRWG QYFRNMKRSR 
GGSKSDKDSV QEGQDSDAEV SFPDEPSLAE MGPANGLYGS LGEPTQALGR PSGALGNFSL 
EHGGLAGPEQ YRELRPGSPY GVPPSPAAPQ SLPGPQPLLS SLVYPDTSLG LVPSGAPGGP 
PPMRVLAGNG PSSDLSTGSS GGYPDFPASP ASWLDEVDHA QF