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    NOTCH3 notch receptor 3 [ Homo sapiens (human) ]

    Gene ID: 4854, updated on 2-Nov-2024

    Summary

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    Official Symbol
    NOTCH3provided by HGNC
    Official Full Name
    notch receptor 3provided by HGNC
    Primary source
    HGNC:HGNC:7883
    See related
    Ensembl:ENSG00000074181 MIM:600276; AllianceGenome:HGNC:7883
    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
    IMF2; LMNS; CASIL; CADASIL; CADASIL1
    Summary
    This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]
    Expression
    Broad expression in fat (RPKM 35.4), placenta (RPKM 33.8) and 22 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See NOTCH3 in Genome Data Viewer
    Location:
    19p13.12
    Exon count:
    33
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 19 NC_000019.10 (15159038..15200995, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 19 NC_060943.1 (15283989..15325912, complement)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 19 NC_000019.9 (15269849..15311806, complement)

    Chromosome 19 - NC_000019.10Genomic Context describing neighboring genes Neighboring gene RNA, U6 small nuclear 782, pseudogene Neighboring gene olfactory receptor family 10 subfamily B member 1 pseudogene Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr19:15281145-15281735 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10267 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr19:15291996-15292515 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr19:15292516-15293034 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:15296283-15296783 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:15305376-15305876 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:15305877-15306377 Neighboring gene microRNA 6795 Neighboring gene ReSE screen-validated silencer GRCh37_chr19:15310876-15311102 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:15311689-15312190 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:15312191-15312690 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr19:15333321-15334017 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10268 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:15343009-15343510 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10269 Neighboring gene epoxide hydrolase 3 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:15361355-15362226 Neighboring gene bromodomain containing 4 Neighboring gene ReSE screen-validated silencer GRCh37_chr19:15373316-15373494 Neighboring gene H3K27ac hESC enhancer GRCh37_chr19:15374509-15375008 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:15376180-15376680 Neighboring gene H3K27ac hESC enhancer GRCh37_chr19:15385287-15385786 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 14182 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 14183 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr19:15409795-15410322 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr19:15410749-15411456 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10270 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10271 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10273 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10272 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10274 Neighboring gene uncharacterized LOC124904643 Neighboring gene H3K27ac hESC enhancer GRCh37_chr19:15443616-15444232 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10276 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 14184 Neighboring gene A-kinase anchoring 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 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. Notch signaling mediates melanoma-endothelial cell communication and melanoma cell migration. Howard JD, et al. Pigment Cell Melanoma Res, 2013 Sep. PMID 23773728
    2. Genetically proven cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in a 3-year-old. Benabu Y, et al. Pediatr Radiol, 2013 Sep. PMID 23460375
    3. Unusual clinical presentations in subjects carrying novel NOTCH3 gene mutations. Spinicci G, et al. J Stroke Cerebrovasc Dis, 2013 May. PMID 23465844
    4. "CADASIL coma" in an Italian homozygous CADASIL patient: comparison with clinical and MRI findings in age-matched heterozygous patients with the same G528C NOTCH3 mutation. Ragno M, et al. Neurol Sci, 2013 Nov. PMID 23572112
    5. Brain microvascular accumulation and distribution of the NOTCH3 ectodomain and granular osmiophilic material in CADASIL. Yamamoto Y, et al. J Neuropathol Exp Neurol, 2013 May. PMID 23584202

    See all (505) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Clinical and neuroradiological spectrum of biallelic variants in NOTCH3.
      Title: Clinical and neuroradiological spectrum of biallelic variants in NOTCH3.
    2. NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke.
      Title: NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke.
    3. Pro-Hemorrhagic Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Associated with NOTCH3 p.R75P Mutation with Low Vascular NOTCH3 Aggregation Property.
      Title: Pro-Hemorrhagic Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Associated with NOTCH3 p.R75P Mutation with Low Vascular NOTCH3 Aggregation Property.
    4. Phenotypes Associated with NOTCH3 Cysteine-Sparing Mutations in Patients with Clinical Suspicion of CADASIL: A Systematic Review.
      Title: Phenotypes Associated with NOTCH3 Cysteine-Sparing Mutations in Patients with Clinical Suspicion of CADASIL: A Systematic Review.
    5. Mutant NOTCH3ECD Triggers Defects in Mitochondrial Function and Mitophagy in CADASIL Cell Models.
      Title: Mutant NOTCH3ECD Triggers Defects in Mitochondrial Function and Mitophagy in CADASIL Cell Models.
    6. A NOTCH3-CXCL12-driven myeloma-tumor niche signaling axis promotes chemoresistance in multiple myeloma.
      Title: A NOTCH3-CXCL12-driven myeloma-tumor niche signaling axis promotes chemoresistance in multiple myeloma.
    7. Nailfold capillary measurements correlated to NOTCH3 R544C mutation in preclinical CADASIL patients.
      Title: Nailfold capillary measurements correlated to NOTCH3 R544C mutation in preclinical CADASIL patients.
    8. Single-Cell Analysis Identifies NOTCH3-Mediated Interactions between Stromal Cells That Promote Microenvironment Remodeling and Invasion in Lung Adenocarcinoma.
      Title: Single-Cell Analysis Identifies NOTCH3-Mediated Interactions between Stromal Cells That Promote Microenvironment Remodeling and Invasion in Lung Adenocarcinoma.
    9. Myofibrillogenesis Regulator-1 Regulates the Ubiquitin Lysosomal Pathway of Notch3 Intracellular Domain Through E3 Ubiquitin-Protein Ligase Itchy Homolog in the Metastasis of Non-Small Cell Lung Cancer.
      Title: Myofibrillogenesis Regulator-1 Regulates the Ubiquitin Lysosomal Pathway of Notch3 Intracellular Domain Through E3 Ubiquitin-Protein Ligase Itchy Homolog in the Metastasis of Non-Small Cell Lung Cancer.
    10. Association of Rare NOTCH3 Variants With Prevalent and Incident Stroke and Dementia in the General Population.
      Title: Association of Rare NOTCH3 Variants With Prevalent and Incident Stroke and Dementia in the General Population.
    Submit: New GeneRIF Correction See all GeneRIFs (436)

    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

    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

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables cadherin binding HDA PubMed 
    enables calcium ion binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables enzyme binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables identical protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables signaling receptor activity IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in Notch signaling pathway IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in artery morphogenesis IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in axon guidance IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in forebrain development IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in glomerular capillary formation IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in negative regulation of neuron differentiation IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in negative regulation of transcription by RNA polymerase II IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in neuroblast differentiation IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in neuron fate commitment IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in positive regulation of miRNA transcription IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in positive regulation of smooth muscle cell proliferation IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in positive regulation of transcription by RNA polymerase II IEA
    Inferred from Electronic Annotation
    more info
    		  
    Component Evidence Code Pubs
    located_in Golgi membrane TAS
    Traceable Author Statement
    more info
    		  
    is_active_in cell surface IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in cytosol TAS
    Traceable Author Statement
    more info
    		  
    located_in endoplasmic reticulum membrane TAS
    Traceable Author Statement
    more info
    		  
    located_in extracellular region TAS
    Traceable Author Statement
    more info
    		  
    located_in nucleoplasm IDA
    Inferred from Direct Assay
    more info
    		  
    located_in nucleoplasm TAS
    Traceable Author Statement
    more info
    		  
    is_active_in plasma membrane IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in plasma membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in plasma membrane TAS
    Traceable Author Statement
    more info
    		  
    part_of receptor complex IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    part_of receptor complex IDA
    Inferred from Direct Assay
    more info
    		 PubMed 

    General protein information

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    Preferred Names
    neurogenic locus notch homolog protein 3
    Names
    Notch homolog 3
    notch 3

    NCBI Reference Sequences (RefSeq)

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    NEW Try the new Transcript table

    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_009819.1 RefSeqGene

      Range
      4987..46944
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_000435.3 → NP_000426.2  neurogenic locus notch homolog protein 3 precursor

      See identical proteins and their annotated locations for NP_000426.2

      Status: REVIEWED

      Source sequence(s)
      AC004257, AC004663, U97669
      Consensus CDS
      CCDS12326.1
      UniProtKB/Swiss-Prot
      Q9UEB3, Q9UM47, Q9UPL3, Q9Y6L8
      Related
      ENSP00000263388.1, ENST00000263388.7
      Conserved Domains (11) summary
      smart00179
      Location:657 → 686
      EGF_CA; Calcium-binding EGF-like domain
      COG0666
      Location:1777 → 1893
      ANKYR; Ankyrin repeat [Signal transduction mechanisms]
      cd00054
      Location:158 → 195
      EGF_CA; Calcium-binding EGF-like domain, present in a large number of membrane-bound and extracellular (mostly animal) proteins. Many of these proteins require calcium for their biological function and calcium-binding sites have been found to be located at the ...
      cd00204
      Location:1866 → 1992
      ANK; ankyrin repeats; ankyrin repeats mediate protein-protein interactions in very diverse families of proteins. The number of ANK repeats in a protein can range from 2 to over 20 (ankyrins, for example). ANK repeats may occur in combinations with other ...
      pfam00066
      Location:1425 → 1459
      Notch; LNR domain
      pfam06816
      Location:1508 → 1557
      NOD; NOTCH protein
      pfam07684
      Location:1578 → 1637
      NODP; NOTCH protein
      pfam11936
      Location:2212 → 2273
      DUF3454; Domain of unknown function (DUF3454)
      pfam12796
      Location:1910 → 2002
      Ank_2; Ankyrin repeats (3 copies)
      pfam13857
      Location:1858 → 1913
      Ank_5; Ankyrin repeats (many copies)
      sd00045
      Location:1905 → 1936
      ANK; ANK repeat [structural motif]

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

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

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000019.10 Reference GRCh38.p14 Primary Assembly

      Range
      15159038..15200995 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_005259924.5 → XP_005259981.1  neurogenic locus notch homolog protein 3 isoform X1

      Conserved Domains (10) summary
      COG0666
      Location:1725 → 1841
      ANKYR; Ankyrin repeat [Signal transduction mechanisms]
      cd00054
      Location:158 → 195
      EGF_CA; Calcium-binding EGF-like domain, present in a large number of membrane-bound and extracellular (mostly animal) proteins. Many of these proteins require calcium for their biological function and calcium-binding sites have been found to be located at the ...
      cd00204
      Location:1814 → 1940
      ANK; ankyrin repeats; ankyrin repeats mediate protein-protein interactions in very diverse families of proteins. The number of ANK repeats in a protein can range from 2 to over 20 (ankyrins, for example). ANK repeats may occur in combinations with other ...
      pfam00066
      Location:1373 → 1407
      Notch; LNR domain
      pfam06816
      Location:1456 → 1505
      NOD; NOTCH protein
      pfam07684
      Location:1526 → 1585
      NODP; NOTCH protein
      pfam11936
      Location:2160 → 2221
      DUF3454; Domain of unknown function (DUF3454)
      pfam12796
      Location:1858 → 1950
      Ank_2; Ankyrin repeats (3 copies)
      pfam13857
      Location:1806 → 1861
      Ank_5; Ankyrin repeats (many copies)
      sd00045
      Location:1853 → 1884
      ANK; ANK repeat [structural motif]

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060943.1 Alternate T2T-CHM13v2.0

      Range
      15283989..15325912 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054321104.1 → XP_054177079.1  neurogenic locus notch homolog protein 3 isoform X1

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q9UM47.2 GenPept UniProtKB/Swiss-Prot:Q9UM47

    Gene LinkOut

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

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