Details for: RFT1

Gene ID: 91869

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: RFT1

Ensembl ID: ENSG00000163933

Description: RFT1 homolog

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • cerebral cortex endothelial cell CL1001602
    CSI 3.18
    rCSI 5.5%
    PRS 94.3
  • granulocyte monocyte progenitor cell CL0000557
    CSI 2.89
    rCSI 2.5%
    PRS 97.61
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 2.82
    rCSI 2.55%
    PRS 96.45
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 2.42
    rCSI 3.01%
    PRS 88.99
  • sst GABAergic cortical interneuron CL4023017
    CSI 2.35
    rCSI 3.03%
    PRS 91.23
  • placental villous trophoblast CL2000060
    CSI 2.32
    rCSI 3.58%
    PRS 95.49
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 2.02
    rCSI 3.39%
    PRS 90.63
  • erythroid progenitor cell CL0000038
    CSI 0.43
    rCSI 2.45%
    PRS 97.53

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 [RFT1](/details-gene/91869) (RFT1 Homolog) is a protein-coding gene located on chromosome 3p21.1. It encodes an essential component of the N-linked glycosylation pathway, a fundamental process for the proper folding and function of a vast number of proteins. Functioning as a glycolipid floppase in the endoplasmic reticulum membrane, [RFT1](/details-gene/91869) is responsible for translocating the dolichol-linked oligosaccharide precursor from the cytoplasm into the ER lumen, a rate-limiting step in protein glycosylation. Its broad expression in diverse and metabolically active cell types, including endothelial cells, hematopoietic progenitors, and cortical interneurons, underscores its critical housekeeping role. Mutations in [RFT1](/details-gene/91869) are known to cause Congenital Disorder of Glycosylation, type In (CDG-In), a severe multisystemic disorder, highlighting its indispensable role in human development and cellular function ([Link](https://doi.org/10.1016/j.ajhg.2007.12.021)). ## Cellular Roles and Expression Landscape The expression profile of [RFT1](/details-gene/91869) suggests it plays a vital role in a wide array of specialized cells that are characterized by high rates of protein synthesis, secretion, or complex membrane dynamics. **Overall**, the gene shows significant expression (CSI > 2.0) in seemingly disparate cell lineages, pointing to a foundational rather than a lineage-specific function. Its highest significance is observed in [cerebral cortex endothelial cell](/details-cell/CL1001602) (CSI: 3.18), which may reflect the high demand for glycosylated membrane proteins essential for maintaining the blood-brain barrier. Furthermore, [RFT1](/details-gene/91869) is highly significant in multiple hematopoietic progenitor populations, including [granulocyte monocyte progenitor cell](/details-cell/CL0000557) (CSI: 2.89) and [megakaryocyte-erythroid progenitor cell](/details-cell/CL0000050) (CSI: 2.82), which is consistent with the extensive protein synthesis required for cell proliferation and differentiation in the bone marrow. The gene is also a notable marker in several subtypes of inhibitory neurons, such as [pvalb GABAergic cortical interneuron](/details-cell/CL4023018) (CSI: 2.42) and [sst GABAergic cortical interneuron](/details-cell/CL4023017) (CSI: 2.35), suggesting that robust N-glycosylation is critical for the function of synaptic proteins and ion channels in these cells. ## Pathways and Molecular Function Functional annotations confirm the central role of [RFT1](/details-gene/91869) in protein modification. The gene product is localized to the [endoplasmic reticulum membrane](/details-component/GO:0005789) and possesses [glycolipid floppase activity](/details-function/GO:0034202). This specific function is a critical step in the [dolichol-linked oligosaccharide biosynthetic process](/details-process/GO:0006488), which provides the glycan precursor for [protein n-linked glycosylation](/details-process/GO:0006487). Reactome pathways further elaborate on this role, placing [RFT1](/details-gene/91869) squarely within the [Asparagine n-linked glycosylation](/details-pathway/R-HSA-446203) cascade, specifically in the [biosynthesis of the n-glycan precursor](/details-pathway/R-HSA-446193). The clinical importance of this function is highlighted by its direct association with the pathway [Defective rft1 causes cdg-1n](/details-pathway/R-HSA-4570571), a sub-pathway within [Diseases of glycosylation](/details-pathway/R-HSA-3781865). This indicates that disruption of this single gene's function leads to a systemic failure in the [post-translational protein modification](/details-pathway/R-HSA-597592) machinery, resulting in a severe metabolic disease phenotype ([Link](https://doi.org/10.1002/humu.21085)). ## Research Directions Given that [RFT1](/details-gene/91869) is a fundamental housekeeping gene, research should focus on understanding the cell-type-specific consequences of its dysfunction and exploring therapeutic strategies for its associated disorders. **Proposed Hypotheses:** 1. The high significance of [RFT1](/details-gene/91869) in hematopoietic progenitors suggests that its activity level is a critical determinant of differentiation efficiency. We hypothesize that subtle reductions in [RFT1](/details-gene/91869) expression could impair hematopoiesis by disrupting the proper glycosylation and surface expression of key cytokine receptors and adhesion molecules necessary for lineage commitment. 2. Given its prominent expression in specific GABAergic interneuron subtypes, we hypothesize that [RFT1](/details-gene/91869)-mediated glycosylation is essential for the stability and trafficking of specific synaptic proteins, such as GABA-A receptors or voltage-gated ion channels. A deficiency in [RFT1](/details-gene/91869) in these neurons could lead to an excitatory/inhibitory imbalance in cortical circuits, contributing to the neurological symptoms observed in CDG-In patients. **Experimental Approach:** To test the second hypothesis, a conditional knockout mouse model could be generated using a Cre-Lox system to specifically delete [RFT1](/details-gene/91869) in Pvalb- or Sst-expressing interneurons. Electrophysiological analysis, such as whole-cell patch-clamp recordings from cortical slices, would be performed to measure changes in inhibitory postsynaptic currents and overall neuronal excitability. Concurrently, quantitative mass spectrometry-based glycoproteomics on isolated interneurons from these mice could identify specific receptor and channel substrates whose glycosylation status and abundance are altered, directly linking [RFT1](/details-gene/91869) function to synaptic protein integrity. **Therapeutic Potential:** As [RFT1](/details-gene/91869) is an essential enzyme whose loss-of-function causes severe disease, it is not a candidate for therapeutic inhibition. Instead, its therapeutic potential lies in strategies aimed at restoring or augmenting its function. For patients with hypomorphic mutations leading to reduced but not absent RFT1 protein, small molecule chaperones that stabilize the mutant protein and enhance its residual floppase activity could be a viable approach. For patients with null mutations, gene replacement therapy using AAV vectors to deliver a functional copy of the [RFT1](/details-gene/91869) gene represents a potential, albeit challenging, long-term strategy, particularly for mitigating the severe neurological aspects of CDG-In.

Genular Protein ID: 1732602494

Symbol: RFT1_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q96AA3 Q96J03

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 4 Ensembl 1 ExpressionAtlas 1 GO 5 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 1 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 2 RefSeq 1 SMR 1 STRING 1 SignaLink 1 SwissPalm 1 TCDB 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 12200473

Title: Common origin and evolution of glycosyltransferases using Dol-P-monosaccharides as donor substrate.

PubMed ID: 12200473

DOI: 10.1093/oxfordjournals.molbev.a004208

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: 18313027

Title: Human RFT1 deficiency leads to a disorder of N-linked glycosylation.

PubMed ID: 18313027

DOI: 10.1016/j.ajhg.2007.12.021

PubMed ID: 25944712

Title: N-terminome analysis of the human mitochondrial proteome.

PubMed ID: 25944712

DOI: 10.1002/pmic.201400617

PubMed ID: 19701946

Title: RFT1 deficiency in three novel CDG patients.

PubMed ID: 19701946

DOI: 10.1002/humu.21085

Sequence Information:

  • Length: 541
  • Mass: 60335
  • Checksum: 2988BA1A2EB769E0
  • Sequence:
    • MGSQEVLGHA ARLASSGLLL QVLFRLITFV LNAFILRFLS KEIVGVVNVR LTLLYSTTLF 
LAREAFRRAC LSGGTQRDWS QTLNLLWLTV PLGVFWSLFL GWIWLQLLEV PDPNVVPHYA 
TGVVLFGLSA VVELLGEPFW VLAQAHMFVK LKVIAESLSV ILKSVLTAFL VLWLPHWGLY 
IFSLAQLFYT TVLVLCYVIY FTKLLGSPES TKLQTLPVSR ITDLLPNITR NGAFINWKEA 
KLTWSFFKQS FLKQILTEGE RYVMTFLNVL NFGDQGVYDI VNNLGSLVAR LIFQPIEESF 
YIFFAKVLER GKDATLQKQE DVAVAAAVLE SLLKLALLAG LTITVFGFAY SQLALDIYGG 
TMLSSGSGPV LLRSYCLYVL LLAINGVTEC FTFAAMSKEE VDRYNFVMLA LSSSFLVLSY 
LLTRWCGSVG FILANCFNMG IRITQSLCFI HRYYRRSPHR PLAGLHLSPV LLGTFALSGG 
VTAVSEVFLC CEQGWPARLA HIAVGAFCLG ATLGTAFLTE TKLIHFLRTQ LGVPRRTDKM 
T