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    NALCN sodium leak channel, non-selective [ Homo sapiens (human) ]

    Gene ID: 259232, updated on 3-Apr-2024

    Summary

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    Official Symbol
    NALCNprovided by HGNC
    Official Full Name
    sodium leak channel, non-selectiveprovided by HGNC
    Primary source
    HGNC:HGNC:19082
    See related
    Ensembl:ENSG00000102452 MIM:611549; AllianceGenome:HGNC:19082
    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
    IHPRF; INNFD; CanIon; IHPRF1; VGCNL1; CLIFAHDD; bA430M15.1
    Summary
    This gene encodes a voltage-independent, nonselective cation channel which belongs to a family of voltage-gated sodium and calcium channels that regulates the resting membrane potential and excitability of neurons. This family is expressed throughout the nervous system and conducts a persistent sodium leak current that contributes to tonic neuronal excitability. The encoded protein forms a channelosome complex that includes G-protein-coupled receptors, UNC-79, UNC-80, NCA localization factor-1, and src family tyrosine kinases. Naturally occurring mutations in this gene are associated with infantile neuroaxonal dystrophy, infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) syndrome, and congenital contractures of the limbs and face with hypotonia and developmental delay (CLIFAHDD) syndrome. A knockout of the orthologous gene in mice results in paralysis with a severely disrupted respiratory rhythm, and lethality within 24 hours after birth. [provided by RefSeq, Apr 2017]
    Expression
    Biased expression in brain (RPKM 11.1), adrenal (RPKM 2.5) and 5 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See NALCN in Genome Data Viewer
    Location:
    13q32.3-q33.1
    Exon count:
    48
    Annotation release Status Assembly Chr Location
    RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 13 NC_000013.11 (101053776..101417179, complement)
    RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 13 NC_060937.1 (100268892..100632422, complement)
    105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 13 NC_000013.10 (101706128..102068859, complement)

    Chromosome 13 - NC_000013.11Genomic Context describing neighboring genes Neighboring gene NALCN antisense RNA 1 Neighboring gene Sharpr-MPRA regulatory region 9290 Neighboring gene ADP ribosylation factor 4 pseudogene 3 Neighboring gene long intergenic non-protein coding RNA 411 Neighboring gene H3K27ac hESC enhancer GRCh37_chr13:101698875-101699376 Neighboring gene BRD4-independent group 4 enhancer GRCh37_chr13:101701141-101702340 Neighboring gene uncharacterized LOC124903202 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr13:101717146-101717646 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr13:101717647-101718147 Neighboring gene P300/CBP strongly-dependent group 1 enhancer GRCh37_chr13:101909917-101911116 Neighboring gene NANOG hESC enhancer GRCh37_chr13:101986545-101987100 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr13:102068211-102068761 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr13:102067660-102068210 Neighboring gene Sharpr-MPRA regulatory region 15039 Neighboring gene P300/CBP strongly-dependent group 1 enhancer GRCh37_chr13:102102071-102103270 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr13:102104604-102105108 Neighboring gene H3K27ac hESC enhancer GRCh37_chr13:102126208-102126708 Neighboring gene Sharpr-MPRA regulatory region 3234 Neighboring gene integrin subunit beta like 1 Neighboring gene ReSE screen-validated silencer GRCh37_chr13:102341159-102341390 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr13:102360299-102360823 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 7963 Neighboring gene NANOG hESC enhancer GRCh37_chr13:102403785-102404286 Neighboring gene fibroblast growth factor 14 Neighboring gene RNA, U1 small nuclear 24, pseudogene

    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. Case Report: A de novo Variant in NALCN Associated With CLIFAHDD Syndrome in a Chinese Infant. Liao Z, et al. Front Pediatr, 2022. PMID 35911839, Free PMC Article
    2. Structural architecture of the human NALCN channelosome. Kschonsak M, et al. Nature, 2022 Mar. PMID 34929720
    3. A homozygous truncating NALCN variant in two Afro-Caribbean siblings with hypotonia and dolichocephaly. Ope O, et al. Am J Med Genet A, 2020 Aug. PMID 32618095
    4. Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties. Bouasse M, et al. Sci Rep, 2019 Aug 13. PMID 31409833, Free PMC Article
    5. Periodic breathing in patients with NALCN mutations. Bourque DK, et al. J Hum Genet, 2018 Oct. PMID 29968795

    See all (55) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN.
      Title: New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN.
    2. Extending and outlining the genotypic and phenotypic spectrum of novel mutations of NALCN gene in IHPRF1 syndrome: identifying recurrent urinary tract infection.
      Title: Extending and outlining the genotypic and phenotypic spectrum of novel mutations of NALCN gene in IHPRF1 syndrome: identifying recurrent urinary tract infection.
    3. Structural architecture of the human NALCN channelosome.
      Title: Structural architecture of the human NALCN channelosome.
    4. A homozygous truncating NALCN variant in two Afro-Caribbean siblings with hypotonia and dolichocephaly.
      Title: A homozygous truncating NALCN variant in two Afro-Caribbean siblings with hypotonia and dolichocephaly.
    5. Structure of the human sodium leak channel NALCN.
      Title: Structure of the human sodium leak channel NALCN.
    6. Structure of the human sodium leak channel NALCN in complex with FAM155A.
      Title: Structure of the human sodium leak channel NALCN in complex with FAM155A.
    7. Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties.
      Title: Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties.
    8. Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex.
      Title: Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex.
    9. PRMT7-mediated NALCN inhibition provides a potential target for the development of therapeutic tools for neurological diseases
      Title: Methylation determines the extracellular calcium sensitivity of the leak channel NALCN in hippocampal dentate granule cells.
    10. these are the first European cases with Infantile hypotonia with psychomotor retardation and characteristic facies-1 syndrome with biallelic truncating mutations of NALCN.
      Title: Novel NALCN biallelic truncating mutations in siblings with IHPRF1 syndrome.
    Submit: New GeneRIF Correction See all GeneRIFs (30)

    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
    A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder.
    EBI GWAS Catalog
    Genome-wide association study of atypical psychosis.
    EBI GWAS Catalog
    Genome-wide association study of neurocognitive impairment and dementia in HIV-infected adults.
    EBI GWAS Catalog
    Prognostic implications of genetic variants in advanced non-small cell lung cancer: a 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

    • FLJ23913, FLJ44659, FLJ44764, MGC74524

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables leak channel activity ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    enables monoatomic cation channel activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables monoatomic cation channel activity ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables sodium channel activity TAS
    Traceable Author Statement
    more info
    		  
    enables voltage-gated sodium channel activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables voltage-gated sodium channel activity IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in calcium ion transmembrane transport ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in monoatomic ion transmembrane transport TAS
    Traceable Author Statement
    more info
    		  
    involved_in positive regulation of synaptic transmission, GABAergic IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in positive regulation of synaptic transmission, cholinergic IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in potassium ion transmembrane transport ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in regulation of resting membrane potential ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in sodium ion transmembrane transport ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    Component Evidence Code Pubs
    part_of monoatomic ion channel complex IEA
    Inferred from Electronic Annotation
    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
    		  

    General protein information

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    Preferred Names
    sodium leak channel NALCN
    Names
    four repeat voltage-gated ion channel
    voltage gated channel like 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_053176.1 RefSeqGene

      Range
      5699..368431
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001350748.2 → NP_001337677.1  sodium leak channel NALCN isoform 1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (1).
      Source sequence(s)
      AL138707, AL354891, AL356778, BF516239, KF511189
      Consensus CDS
      CCDS91832.1
      UniProtKB/TrEMBL
      A0A6Q8PFS9, A0A976XH31
      Related
      ENSP00000501955.1, ENST00000675332.1
      Conserved Domains (1) summary
      pfam00520
      Location:916 → 1190
      Ion_trans; Ion transport protein

    2. NM_001350749.2 → NP_001337678.1  sodium leak channel NALCN isoform 2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) uses an alternate splice site in the 5' UTR and lacks an alternate exon in the 5' coding region but maintains the reading frame, compared to variant 1. The encoded isoform (2) is shorter than isoform 1. Both variants 2 and 3 encode the same isoform (2).
      Source sequence(s)
      AL138707, AL354891, AL356778, BF516239, KF511189
      Consensus CDS
      CCDS9498.1
      UniProtKB/Swiss-Prot
      Q6P2S6, Q6ZMI7, Q8IZF0, Q8IZZ1, Q8TAH1
      UniProtKB/TrEMBL
      A0A976XH31
      Conserved Domains (1) summary
      pfam00520
      Location:887 → 1161
      Ion_trans; Ion transport protein

    3. NM_001350750.2 → NP_001337679.1  sodium leak channel NALCN isoform 3

      Status: REVIEWED

      Description
      Transcript Variant: This variant (4) lacks two alternate exons in the 5' coding region but maintains the reading frame, compared to variant 1. The encoded isoform (3) is shorter than isoform 1. Both variants 4 and 5 encode the same isoform (3).
      Source sequence(s)
      AL138707, AL354891, AL356778, BF516239, KF511189
      Consensus CDS
      CCDS91831.1
      UniProtKB/TrEMBL
      A0A6Q8PF19, A0A976XH31
      Related
      ENSP00000501603.1, ENST00000676315.1
      Conserved Domains (1) summary
      pfam00520
      Location:858 → 1132
      Ion_trans; Ion transport protein

    4. NM_001350751.2 → NP_001337680.1  sodium leak channel NALCN isoform 3

      Status: REVIEWED

      Description
      Transcript Variant: This variant (5) uses an alternate splice site in the 5' UTR and lacks two alternate exons in the 5' coding region but maintains the reading frame, compared to variant 1. The encoded isoform (3) is shorter than isoform 1. Both variants 4 and 5 encode the same isoform (3).
      Source sequence(s)
      AL138707, AL354891, AL356778, BF516239, KF511189
      Consensus CDS
      CCDS91831.1
      UniProtKB/TrEMBL
      A0A6Q8PF19, A0A976XH31
      Conserved Domains (1) summary
      pfam00520
      Location:858 → 1132
      Ion_trans; Ion transport protein

    5. NM_052867.4 → NP_443099.1  sodium leak channel NALCN isoform 2

      See identical proteins and their annotated locations for NP_443099.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks an alternate exon in the 5' coding region but maintains the reading frame, compared to variant 1. The encoded isoform (2) is shorter than isoform 1. Both variants 2 and 3 encode the same isoform (2).
      Source sequence(s)
      AK002089, AL356778, AY141972, BC012128, BF516239, DA128114
      Consensus CDS
      CCDS9498.1
      UniProtKB/Swiss-Prot
      Q6P2S6, Q6ZMI7, Q8IZF0, Q8IZZ1, Q8TAH1
      UniProtKB/TrEMBL
      A0A976XH31
      Related
      ENSP00000251127.6, ENST00000251127.11
      Conserved Domains (1) summary
      pfam00520
      Location:887 → 1161
      Ion_trans; Ion transport protein

    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_000013.11 Reference GRCh38.p14 Primary Assembly

      Range
      101053776..101417179 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_011521069.3 → XP_011519371.1  sodium leak channel NALCN isoform X2

      UniProtKB/TrEMBL
      A0A976XH31
      Conserved Domains (2) summary
      pfam00520
      Location:1224 → 1448
      Ion_trans; Ion transport protein
      pfam10688
      Location:1256 → 1401
      Imp-YgjV; Bacterial inner membrane protein

    2. XM_011521067.3 → XP_011519369.1  sodium leak channel NALCN isoform X1

      UniProtKB/TrEMBL
      A0A976XH31
      Conserved Domains (2) summary
      pfam00520
      Location:1253 → 1477
      Ion_trans; Ion transport protein
      pfam10688
      Location:1285 → 1430
      Imp-YgjV; Bacterial inner membrane protein

    3. XM_024449336.2 → XP_024305104.1  sodium leak channel NALCN isoform X5

      UniProtKB/TrEMBL
      A0A976XH31
      Conserved Domains (1) summary
      pfam00520
      Location:935 → 1209
      Ion_trans; Ion transport protein

    4. XM_017020536.3 → XP_016876025.1  sodium leak channel NALCN isoform X3

      UniProtKB/TrEMBL
      A0A976XH31

    5. XM_017020537.2 → XP_016876026.1  sodium leak channel NALCN isoform X4

      UniProtKB/TrEMBL
      A0A976XH31

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060937.1 Alternate T2T-CHM13v2.0

      Range
      100268892..100632422 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054374412.1 → XP_054230387.1  sodium leak channel NALCN isoform X1

    2. XM_054374416.1 → XP_054230391.1  sodium leak channel NALCN isoform X5

    3. XM_054374413.1 → XP_054230388.1  sodium leak channel NALCN isoform X2

    4. XM_054374414.1 → XP_054230389.1  sodium leak channel NALCN isoform X3

    5. XM_054374415.1 → XP_054230390.1  sodium leak channel NALCN isoform X4

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q8IZF0.1 GenPept UniProtKB/Swiss-Prot:Q8IZF0

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