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    GGCX gamma-glutamyl carboxylase [ Homo sapiens (human) ]

    Gene ID: 2677, updated on 3-Apr-2024

    Summary

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    Official Symbol
    GGCXprovided by HGNC
    Official Full Name
    gamma-glutamyl carboxylaseprovided by HGNC
    Primary source
    HGNC:HGNC:4247
    See related
    Ensembl:ENSG00000115486 MIM:137167; AllianceGenome:HGNC:4247
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    VKCFD1
    Summary
    This gene encodes an integral membrane protein of the rough endoplasmic reticulum that carboxylates glutamate residues of vitamin K-dependent proteins to gamma carboxyl glutamate, a modification that is required for their activity. The vitamin K-dependent protein substrates have a propeptide that binds the enzyme, with carbon dioxide, dioxide, and reduced vitamin K acting as co-substrates. Vitamin K-dependent proteins affect a number of physiologic processes including blood coagulation, prevention of vascular calcification, and inflammation. Allelic variants of this gene have been associated with pseudoxanthoma elasticum-like disorder with associated multiple coagulation factor deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]
    Expression
    Ubiquitous expression in liver (RPKM 18.5), thyroid (RPKM 16.4) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    Location:
    2p11.2
    Exon count:
    15
    Annotation release Status Assembly Chr Location
    RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 2 NC_000002.12 (85544720..85561493, complement)
    RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 2 NC_060926.1 (85546779..85563552, complement)
    105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 2 NC_000002.11 (85771843..85788616, complement)

    Chromosome 2 - NC_000002.12Genomic Context describing neighboring genes Neighboring gene ribosomal protein SA pseudogene 22 Neighboring gene ReSE screen-validated silencer GRCh37_chr2:85740471-85740650 Neighboring gene ReSE screen-validated silencer GRCh37_chr2:85754312-85754503 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16127 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16128 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16129 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11701 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11702 Neighboring gene promoter of MAT2A antisense radiation-induced circulating long non-coding RNA Neighboring gene methionine adenosyltransferase 2A Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16130 Neighboring gene NANOG hESC enhancer GRCh37_chr2:85793997-85794515 Neighboring gene RNA, 7SL, cytoplasmic 126, pseudogene Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16131 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16132 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16133 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:85806777-85807430 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:85807431-85808085 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:85808086-85808739 Neighboring gene vesicle associated membrane protein 8

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. [Partial research progress of GGCX pathogenic variation associated phenotypes]. Shen G, et al. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2022 Jun 10. PMID 35773773
    2. GGCX variants leading to biallelic deficiency to γ-carboxylate GRP cause skin laxity in VKCFD1 patients. Ghosh S, et al. Hum Mutat, 2022 Jan. PMID 34816548
    3. γ-Glutamyl carboxylase mutations differentially affect the biological function of vitamin K-dependent proteins. Hao Z, et al. Blood, 2021 Jan 28. PMID 33507293, Free PMC Article
    4. Pseudoxanthoma elasticum-like syndrome with coagulation deficiency associated with carotid artery hypoplasia and a novel gamma-glutamyl carboxylase gene mutation. Guillen-Climent S, et al. Int J Dermatol, 2021 Jan. PMID 32808310
    5. Effect of GGCX on the differentiation function of osteoporosis bone marrow mesenchymal stem cells through regulating TGFβ/smad signaling pathway. Wang QL, et al. Eur Rev Med Pharmacol Sci, 2019 Sep. PMID 31539109

    See all (129) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Association among VKORC1 rs9923231, CYP4F2 rs2108622, GGCX rs11676382 polymorphisms and acute ischemic stroke.
      Title: Association among VKORC1 rs9923231, CYP4F2 rs2108622, GGCX rs11676382 polymorphisms and acute ischemic stroke.
    2. [Partial research progress of GGCX pathogenic variation associated phenotypes].
      Title: [Partial research progress of GGCX pathogenic variation associated phenotypes].
    3. GGCX variants leading to biallelic deficiency to gamma-carboxylate GRP cause skin laxity in VKCFD1 patients.
      Title: GGCX variants leading to biallelic deficiency to γ-carboxylate GRP cause skin laxity in VKCFD1 patients.
    4. Pseudoxanthoma elasticum-like syndrome with coagulation deficiency associated with carotid artery hypoplasia and a novel gamma-glutamyl carboxylase gene mutation.
      Title: Pseudoxanthoma elasticum-like syndrome with coagulation deficiency associated with carotid artery hypoplasia and a novel gamma-glutamyl carboxylase gene mutation.
    5. gamma-Glutamyl carboxylase mutations differentially affect the biological function of vitamin K-dependent proteins.
      Title: γ-Glutamyl carboxylase mutations differentially affect the biological function of vitamin K-dependent proteins.
    6. Effect of GGCX on the differentiation function of osteoporosis bone marrow mesenchymal stem cells through regulating TGFbeta/smad signaling pathway.
      Title: Effect of GGCX on the differentiation function of osteoporosis bone marrow mesenchymal stem cells through regulating TGFβ/smad signaling pathway.
    7. Exon 2 skipping eliminates gamma-glutamyl carboxylase activity, indicating a partial splicing defect in a patient with vitamin K clotting factor deficiency.
      Title: Exon 2 skipping eliminates γ-glutamyl carboxylase activity, indicating a partial splicing defect in a patient with vitamin K clotting factor deficiency.
    8. The risk for ischemic atherothrombotic stroke in patients with the gamma-glutamyl carboxylase T/T genotype was higher than in major C-allele carriers.
      Title: [ANALYSIS OF γ-GLUTAMYL CARBOXYLASE GENE rs2592551 POLYMORPHISM ASSOCIATION WITH ISCHEMIC ATHEROTHROMBOTIC STROKE].
    9. unlike the traditional in vitro GGCX activity assay, allows us to assess the functionality of GGCX using its natural protein substrates in a cellular milieu
      Title: Splice-Site Mutation of Exon 3 Deletion in the Gamma-Glutamyl Carboxylase Gene Causes Inactivation of the Enzyme.
    10. 2 causative GGCX mutations ( c.1889-6G>A and c.1657delA) from the first reported clinical case of a VKCFD patient. The intronic mutation c.1889-6G>A affects GGCX splicing. Functional characterization of these 2 mutations suggests that truncation of GGCX from its C-terminus affects not only substrate binding but also protein stability.
      Title: Molecular basis of the first reported clinical case of congenital combined deficiency of coagulation factors.
    Submit: New GeneRIF Correction See all GeneRIFs (61)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    EBI GWAS Catalog

    Description
    Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study.
    EBI GWAS Catalog

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Genotypes

    Pathways from PubChem

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    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ26629

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables gamma-glutamyl carboxylase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables gamma-glutamyl carboxylase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables gamma-glutamyl carboxylase activity TAS
    Traceable Author Statement
    more info
    		  
    enables vitamin binding IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    Process Evidence Code Pubs
    involved_in blood coagulation TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in peptidyl-glutamic acid carboxylation IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in protein modification process TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in vitamin K metabolic process IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Component Evidence Code Pubs
    is_active_in endoplasmic reticulum membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in endoplasmic reticulum membrane TAS
    Traceable Author Statement
    more info
    		  
    located_in membrane TAS
    Traceable Author Statement
    more info
    		 PubMed 

    General protein information

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    Preferred Names
    vitamin K-dependent gamma-carboxylase
    Names
    peptidyl-glutamate 4-carboxylase
    NP_000812.2
    NP_001135741.1
    NP_001298241.1
    XP_005264316.1
    XP_016859292.1
    XP_047299875.1
    XP_047299876.1
    XP_054197353.1
    XP_054197354.1
    XP_054197355.1
    XP_054197356.1

    NCBI Reference Sequences (RefSeq)

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    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_011811.2 RefSeqGene

      Range
      5042..21815
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_592

    mRNA and Protein(s)

    1. NM_000821.7 → NP_000812.2  vitamin K-dependent gamma-carboxylase isoform 1

      See identical proteins and their annotated locations for NP_000812.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (1).
      Source sequence(s)
      AC016753, BC013979, BM974022, BQ000150, DC296316
      Consensus CDS
      CCDS1978.1
      UniProtKB/Swiss-Prot
      B4DMC5, E9PEE1, P38435, Q14415, Q6GU45
      UniProtKB/TrEMBL
      A7YA96
      Related
      ENSP00000233838.3, ENST00000233838.9
      Conserved Domains (1) summary
      pfam05090
      Location:66 → 502
      VKG_Carbox; Vitamin K-dependent gamma-carboxylase

    2. NM_001142269.4 → NP_001135741.1  vitamin K-dependent gamma-carboxylase isoform 2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks an alternate in-frame exon in the 5' coding region compared to variant 1. It encodes isoform 2, which is shorter than isoform 1.
      Source sequence(s)
      AC016753, AK297397, BC013979, BM974022, BQ000150, DC296316
      Consensus CDS
      CCDS46353.1
      UniProtKB/TrEMBL
      A7YA96
      Related
      ENSP00000408045.3, ENST00000430215.7
      Conserved Domains (2) summary
      smart00752
      Location:15 → 258
      HTTM; Horizontally Transferred TransMembrane Domain
      pfam05090
      Location:15 → 445
      VKG_Carbox; Vitamin K-dependent gamma-carboxylase

    3. NM_001311312.2 → NP_001298241.1  vitamin K-dependent gamma-carboxylase isoform 3

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) lacks lacks several exons and its 3' terminal exon extends past a splice site that is used in variant 1. This results in a novel 3' coding region and 3' UTR compared to variant 1. It encodes isoform 3, which is shorter and has a distinct C-terminus compared to isoform 1.
      Source sequence(s)
      AC016753, BM704752
      Consensus CDS
      CCDS92792.1
      UniProtKB/TrEMBL
      A0A8I5KZ18, A0A8I5QJA4
      Related
      ENSP00000508856.1, ENST00000496962.2
      Conserved Domains (1) summary
      cl02773
      Location:56 → 125
      HTTM; Horizontally Transferred TransMembrane Domain

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000002.12 Reference GRCh38.p14 Primary Assembly

      Range
      85544720..85561493 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_017003803.3 → XP_016859292.1  vitamin K-dependent gamma-carboxylase isoform X2

      UniProtKB/TrEMBL
      A7YA96

    2. XM_005264259.6 → XP_005264316.1  vitamin K-dependent gamma-carboxylase isoform X1

      UniProtKB/TrEMBL
      A7YA96
      Conserved Domains (2) summary
      smart00752
      Location:56 → 315
      HTTM; Horizontally Transferred TransMembrane Domain
      pfam05090
      Location:66 → 502
      VKG_Carbox; Vitamin K-dependent gamma-carboxylase

    3. XM_047443919.1 → XP_047299875.1  vitamin K-dependent gamma-carboxylase isoform X3

      Related
      ENSP00000510264.1, ENST00000693287.1

    4. XM_047443920.1 → XP_047299876.1  vitamin K-dependent gamma-carboxylase isoform X4

      Related
      ENSP00000509369.1, ENST00000691348.1

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060926.1 Alternate T2T-CHM13v2.0

      Range
      85546779..85563552 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054341379.1 → XP_054197354.1  vitamin K-dependent gamma-carboxylase isoform X2

    2. XM_054341378.1 → XP_054197353.1  vitamin K-dependent gamma-carboxylase isoform X1

    3. XM_054341380.1 → XP_054197355.1  vitamin K-dependent gamma-carboxylase isoform X3

    4. XM_054341381.1 → XP_054197356.1  vitamin K-dependent gamma-carboxylase isoform X4

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    P38435.2 GenPept UniProtKB/Swiss-Prot:P38435

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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