Details for: TM6SF2

Gene ID: 53345

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: TM6SF2

Ensembl ID: ENSG00000213996

Description: transmembrane 6 superfamily member 2

Cell Significance Landscape

Associated with

Significant Cells

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

  • intestinal epithelial cell CL0002563
    CSI 6.49
    rCSI 6.78%
    PRS 98.89
  • colon epithelial cell CL0011108
    CSI 6.15
    rCSI 6.44%
    PRS 99.04
  • BEST4+ enteroycte CL4030026
    CSI 5.17
    rCSI 6.43%
    PRS 98.92
  • enterocyte CL0000584
    CSI 4.27
    rCSI 6.88%
    PRS 98.38
  • GABAergic neuron CL0000617
    CSI 4.26
    rCSI 14.27%
    PRS 95.06
  • colonocyte CL1000347
    CSI 3.42
    rCSI 4.9%
    PRS 99.05
  • neural progenitor cell CL0011020
    CSI 3.24
    rCSI 14.25%
    PRS 95.49

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.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

Loading network (please wait)...

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 Transmembrane 6 superfamily member 2, encoded by the [TM6SF2](/details-gene/53345) gene, is a multi-pass membrane protein primarily localized to the endoplasmic reticulum. It plays a critical role in lipid metabolism and homeostasis. Expression data indicates that **Overall**, [TM6SF2](/details-gene/53345) is a highly significant gene in epithelial cells of the gastrointestinal tract, particularly [intestinal epithelial cell](/details-cell/CL0002563) and [colon epithelial cell](/details-cell/CL0011108). This expression pattern, combined with its function, suggests a primary role in processing and transporting lipids absorbed from the diet. Importantly, genetic variants in [TM6SF2](/details-gene/53345) have been strongly associated with nonalcoholic fatty liver disease (NAFLD), myocardial infarction risk, and altered plasma lipid levels, highlighting its clinical relevance in metabolic disorders ([Link](https://doi.org/10.1038/ng.2901), [Link](https://doi.org/10.1038/ng.2926)). ## Cellular Roles and Expression Landscape The expression profile of [TM6SF2](/details-gene/53345) underscores its specialized function in tissues with high lipid metabolic activity. In an **Overall** context, the gene shows the highest significance in cells lining the intestine, including [intestinal epithelial cell](/details-cell/CL0002563) (CSI: 6.49), [colon epithelial cell](/details-cell/CL0011108) (CSI: 6.15), and more specialized subtypes like [BEST4+ enteroycte](/details-cell/CL4030026) (CSI: 5.17) and [enterocyte](/details-cell/CL0000584) (CSI: 4.27). This implicates [TM6SF2](/details-gene/53345) as a key component of the machinery responsible for dietary lipid absorption, processing, and secretion. Interestingly, [TM6SF2](/details-gene/53345) also shows significant expression in certain neural cell types, such as the [GABAergic neuron](/details-cell/CL0000617) (CSI: 4.26) and [neural progenitor cell](/details-cell/CL0011020) (CSI: 3.24). While its primary role appears to be in gut and liver metabolism, this suggests a potential secondary function related to lipid homeostasis within the central nervous system. ## Pathways and Molecular Function Functional annotations are highly consistent with the known role of [TM6SF2](/details-gene/53345) in metabolic health. The gene is principally associated with biological processes such as lipid homeostasis ([GO:0055088](https://www.ebi.ac.uk/QuickGO/term/GO:0055088)), lipid metabolic process ([GO:0006629](https://www.ebi.ac.uk/QuickGO/term/GO:0006629)), and the regulation of this process ([GO:0019216](https://www.ebi.ac.uk/QuickGO/term/GO:0019216)). At the cellular level, its localization to the [endoplasmic reticulum membrane](/details-cell/GO:0005789) and the [endoplasmic reticulum-golgi intermediate compartment membrane](/details-cell/GO:0033116) places it at the central hub of lipid synthesis and lipoprotein assembly. Research has demonstrated that [TM6SF2](/details-gene/53345) is crucial for regulating the secretion of triglycerides from the liver into the bloodstream, likely by influencing the formation of very-low-density lipoprotein (VLDL) particles ([Link](https://doi.org/10.1073/pnas.1323785111)). Loss-of-function variants lead to lipid accumulation within liver cells, a key pathogenic step in the development of NAFLD ([Link](https://doi.org/10.1038/ncomms5309)). ## Research Directions The established link between [TM6SF2](/details-gene/53345) variants and liver disease, coupled with its high expression in gut epithelial cells, presents several key avenues for future investigation. **Proposed Hypotheses:** 1. Given its high significance in [intestinal epithelial cell](/details-cell/CL0002563), [TM6SF2](/details-gene/53345) plays a critical role in the assembly and secretion of chylomicrons, the lipoprotein particles responsible for transporting dietary fats. Disease-associated variants may impair this intestinal function, altering post-meal lipid profiles and contributing to metabolic dysregulation independent of its hepatic role. 2. The expression of [TM6SF2](/details-gene/53345) in [GABAergic neuron](/details-cell/CL0000617) suggests it may regulate local lipid composition in neuronal membranes, potentially affecting neurotransmission or neuronal health. Dysregulation of [TM6SF2](/details-gene/53345) in the brain could contribute to the neurological comorbidities sometimes observed in patients with severe metabolic syndrome. **Experimental Approach:** To test the first hypothesis regarding its intestinal role, one could utilize organoid models derived from human intestinal stem cells. Organoids could be generated from individuals carrying either the wild-type or the NAFLD-associated risk variant of [TM6SF2](/details-gene/53345). Following exposure to a lipid challenge (e.g., oleic acid), one would measure the efficiency of chylomicron secretion by quantifying apolipoprotein B-48 (ApoB-48) levels in the culture medium. Lipidomic analysis of the organoid cells and secreted lipoproteins would further reveal specific defects in triglyceride and cholesterol ester packaging. **Therapeutic Potential:** [TM6SF2](/details-gene/53345) presents a complex therapeutic target. The common disease-associated variant (E167K) causes a loss of function, which leads to fat accumulation in the liver but also to lower circulating levels of atherogenic lipids, a cardiovascular benefit ([Link](https://doi.org/10.1038/ng.2926)). Therefore, simple systemic inhibition of [TM6SF2](/details-gene/53345) is unlikely to be a viable strategy for treating NAFLD, as it would mimic the disease-causing state. Instead, therapeutic efforts might focus on liver-specific gene therapy to restore its function in individuals with risk alleles or on developing small molecules that can stabilize the mutant protein's function specifically in hepatocytes, thereby promoting VLDL secretion and alleviating hepatic steatosis without adversely affecting systemic lipid profiles.

Genular Protein ID: 3093528288

Symbol: TM6S2_HUMAN

Name: Transmembrane 6 superfamily member 2

UniProtKB Accession Codes:

Q9BZW4 Q0IJ64

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 5 Ensembl 1 GO 6 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 2 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhylomeDB 1 Proteomes 1 RNAct 1 RefSeq 1 STRING 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 neXtProt 1

Citations:

PubMed ID: 15057824

Title: The DNA sequence and biology of human chromosome 19.

PubMed ID: 15057824

DOI: 10.1038/nature02399

PubMed ID: 11124529

Title: Cloning of the novel gene TM6SF1 reveals conservation of clusters of paralogous genes between human chromosomes 15q24-q26 and 19p13.3-p12.

PubMed ID: 11124529

DOI: 10.1159/000056784

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: 25566323

Title: TM6SF2 and MAC30, new enzyme homologs in sterol metabolism and common metabolic disease.

PubMed ID: 25566323

DOI: 10.3389/fgene.2014.00439

PubMed ID: 24633158

Title: Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk.

PubMed ID: 24633158

DOI: 10.1038/ng.2926

PubMed ID: 24531328

Title: Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.

PubMed ID: 24531328

DOI: 10.1038/ng.2901

PubMed ID: 24978903

Title: TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease.

PubMed ID: 24978903

DOI: 10.1038/ncomms5309

PubMed ID: 24927523

Title: TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content.

PubMed ID: 24927523

DOI: 10.1073/pnas.1323785111

Sequence Information:

  • Length: 377
  • Mass: 42554
  • Checksum: 56C2576367BBF2DF
  • Sequence:
    • MDIPPLAGKI AALSLSALPV SYALNHVSAL SHPLWVALMS ALILGLLFVA VYSLSHGEVS 
YDPLYAVFAV FAFTSVVDLI IALQEDSYVV GFMEFYTKEG EPYLRTAHGV FICYWDGTVH 
YLLYLAMAGA ICRRKRYRNF GLYWLGSFAM SILVFLTGNI LGKYSSEIRP AFFLTIPYLL 
VPCWAGMKVF SQPRALTRCT ANMVQEEQRK GLLQRPADLA LVIYLILAGF FTLFRGLVVL 
DCPTDACFVY IYQYEPYLRD PVAYPKVQML MYMFYVLPFC GLAAYALTFP GCSWLPDWAL 
VFAGGIGQAQ FSHMGASMHL RTPFTYRVPE DTWGCFFVCN LLYALGPHLL AYRCLQWPAF 
FHQPPPSDPL ALHKKQH

Genular Protein ID: 3580855730

Symbol: Q8N8A7_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q8N8A7

Database IDs:

AlphaFoldDB 1 BioGRID-ORCS 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 4 GO 4 KEGG 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PeptideAtlas 1 PharmGKB 1 RefSeq 1 SAM 2

Citations:

PubMed ID: 11181995

Title: The sequence of the human genome.

PubMed ID: 11181995

DOI: 10.1126/science.1058040

PubMed ID: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

Sequence Information:

  • Length: 213
  • Mass: 22485
  • Checksum: A246A5C01E5D04DA
  • Sequence:
    • MDIPPLAGKI AALSLSALPV SYALNHVSAL SHPLWVALMS ALILGLLFVA VYSLSHGEVS 
YDPLYAVFAV FAFTSVVDLI IALQEDSYVV GFMEFYTKEV LGGRPGSPLP HCPSESPTCP 
HRESHTCAQR TESSSATGMA LFTTSSTWPW PAPSAEGAGG RERVAPDPGR EVASSDGVPG 
QGGARSVCRR NQDASLGLQP GVARRRFQGT SQV