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    CNNM4 cyclin and CBS domain divalent metal cation transport mediator 4 [ Homo sapiens (human) ]

    Gene ID: 26504, updated on 2-Nov-2024

    Summary

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    Official Symbol
    CNNM4provided by HGNC
    Official Full Name
    cyclin and CBS domain divalent metal cation transport mediator 4provided by HGNC
    Primary source
    HGNC:HGNC:105
    See related
    Ensembl:ENSG00000158158 MIM:607805; AllianceGenome:HGNC:105
    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
    ACDP4
    Summary
    This gene encodes a member of the ancient conserved domain containing protein family. Members of this protein family contain a cyclin box motif and have structural similarity to the cyclins. The encoded protein may play a role in metal ion transport. Mutations in this gene are associated with Jalili syndrome which consists of cone-rod dystrophy and amelogenesis imperfecta. [provided by RefSeq, Feb 2010]
    Expression
    Broad expression in colon (RPKM 26.1), thyroid (RPKM 9.4) and 23 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See CNNM4 in Genome Data Viewer
    Location:
    2q11.2
    Exon count:
    12
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 2 NC_000002.12 (96760902..96811874)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 2 NC_060926.1 (97267540..97318504)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 2 NC_000002.11 (97426639..97477611)

    Chromosome 2 - NC_000002.12Genomic Context describing neighboring genes Neighboring gene fer-1 like family member 5 Neighboring gene H3K27ac hESC enhancer GRCh37_chr2:97326800-97327300 Neighboring gene H3K27ac hESC enhancer GRCh37_chr2:97327301-97327801 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:97351655-97352380 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:97359457-97359958 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:97360677-97361221 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:97361222-97361765 Neighboring gene lectin, mannose binding 2 like Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:97404177-97405116 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:97405117-97406054 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16224 Neighboring gene H3K4me1 hESC enhancers GRCh37_chr2:97426686-97427275 and GRCh37_chr2:97427276-97427864 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11775 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16226 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16227 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:97435174-97436108 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16228 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16229 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16230 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16231 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16232 Neighboring gene microRNA 3127 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16233 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11776 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11777 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11778 Neighboring gene CNNM3 divergent transcript Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:97494389-97494889 Neighboring gene uncharacterized LOC124907859 Neighboring gene BRD4-independent group 4 enhancer GRCh37_chr2:97498033-97499232 Neighboring gene cyclin and CBS domain divalent metal cation transport mediator 3

    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. Novel splice site mutation in CNNM4 gene in a family with Jalili syndrome. Cherkaoui Jaouad I, et al. Eur J Med Genet, 2017 May. PMID 28246031
    2. A progressive cone-rod dystrophy and amelogenesis imperfecta: a new syndrome. Jalili IK, et al. J Med Genet, 1988 Nov. PMID 3236352, Free PMC Article
    3. Identification of a locus on chromosome 2q11 at which recessive amelogenesis imperfecta and cone-rod dystrophy cosegregate. Downey LM, et al. Eur J Hum Genet, 2002 Dec. PMID 12461695
    4. An autosomal recessive cone-rod dystrophy associated with amelogenesis imperfecta. Michaelides M, et al. J Med Genet, 2004 Jun. PMID 15173235, Free PMC Article
    5. Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta. Parry DA, et al. Am J Hum Genet, 2009 Feb. PMID 19200525, Free PMC Article

    See all (60) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Dimerization of the CNNM extracellular domain.
      Title: Dimerization of the CNNM extracellular domain.
    2. Novel CNNM4 variant and clinical features of Jalili syndrome.
      Title: Novel CNNM4 variant and clinical features of Jalili syndrome.
    3. CNNM proteins selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells.
      Title: CNNM proteins selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells.
    4. Expanding the genotypic spectrum of Jalili syndrome: Novel CNNM4 variants and uniparental isodisomy in a north American patient cohort.
      Title: Expanding the genotypic spectrum of Jalili syndrome: Novel CNNM4 variants and uniparental isodisomy in a north American patient cohort.
    5. The novel identified variant in CNNM4 is the first report from the Pakistani population. Sequence analysis of CNNM4 revealed a novel missense variant (c.1220G>T, p.Arg407Leu) in exon-1 encoding cystathionine-beta-synthase (CBS) domain.
      Title: A novel pathogenic missense variant in CNNM4 underlying Jalili syndrome: Insights from molecular dynamics simulations.
    6. Jalili Syndrome is a rare cone-rod dystrophy (CORD) and amelogenesis imperfecta (AI), We have further characterized its ocular phenotype, including describing SD-OCT, FAF, and electrophysiological features; and report several novel disease-causing sequence variants.
      Title: Jalili Syndrome: Cross-sectional and Longitudinal Features of Seven Patients With Cone-Rod Dystrophy and Amelogenesis Imperfecta.
    7. Here, we report the 2 first families with Jalili Syndrome in Brazil. Molecular analysis of the first family identified a previously described homozygous mutation (p.Leu324Pro) in exon 1 of CNNM4 gene. In the second family, affected patients demonstrated a compound heterozygous mutation in CNNM4, the p.Leu324Pro and the novel nonsense mutation p.Tyr581*.
      Title: Report of two unrelated families with Jalili syndrome and a novel nonsense heterozygous mutation in CNNM4 gene.
    8. Results identified linkage at chromosome 2p14-2q14 and found a homozygous mutation in the CNNM4 gene (p.R605X) causing Jalili syndrome. The truncated CNNM4 protein starting at R605 significantly increased the rate of apoptosis, and significantly increased the interaction between CNNM4 and IQCB1. This mutation may cause Jalili syndrome by a nonsense-mediated decay mechanism, affecting the function of IQCB1 and apoptosis.
      Title: Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1.
    9. Mutational analysis showed in all three brothers a novel likely pathogenic homozygous missense substitution in exon 1 (c.1076T>C, p.(Leu359Pro)) of CNNM4. Both parents were carriers for the variant.
      Title: Co-occurrence of Jalili syndrome and muscular overgrowth.
    10. We describe three siblings with clinical features of Jalili syndrome with a homozygous missense mutation in exon 4 of CNNM4, c.1781A>G (p.N594S).
      Title: A new familial case of Jalili syndrome caused by a novel mutation in CNNM4.
    Submit: New GeneRIF Correction See all GeneRIFs (22)

    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

    Associated conditions

    Description Tests
    Jalili syndrome
    MedGen: C3495589 OMIM: 217080 GeneReviews: Not available
    		Compare labs

    EBI GWAS Catalog

    Description
    Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.
    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

    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ37746, FLJ42791, KIAA1592

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables magnesium ion transmembrane transporter activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables sodium ion transmembrane transporter activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    Process Evidence Code Pubs
    involved_in enamel mineralization IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in intracellular monoatomic cation homeostasis IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in magnesium ion homeostasis IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in magnesium ion transmembrane transport IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in magnesium ion transport IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in sodium ion transmembrane transport IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in visual perception IEA
    Inferred from Electronic Annotation
    more info
    		  
    Component Evidence Code Pubs
    located_in basolateral plasma membrane IEA
    Inferred from Electronic Annotation
    more info
    		  
    is_active_in plasma membrane IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    part_of protein-containing complex IDA
    Inferred from Direct Assay
    more info
    		 PubMed 

    General protein information

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    Preferred Names
    metal transporter CNNM4
    Names
    ancient conserved domain protein 4
    ancient conserved domain-containing protein 4
    cyclin-M4

    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_016608.1 RefSeqGene

      Range
      5001..55973
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_020184.4 → NP_064569.3  metal transporter CNNM4 precursor

      See identical proteins and their annotated locations for NP_064569.3

      Status: REVIEWED

      Source sequence(s)
      AB046812, BC063295
      Consensus CDS
      CCDS2024.2
      UniProtKB/Swiss-Prot
      B7Z1U0, C7SQM3, C7SQM4, C7SQM5, Q53RE5, Q6P4Q7, Q9H9G3, Q9HCI0, Q9NRN1
      Related
      ENSP00000366275.2, ENST00000377075.3
      Conserved Domains (3) summary
      COG0517
      Location:373 → 500
      CBS; CBS domain [Signal transduction mechanisms]
      cd04590
      Location:382 → 502
      CBS_pair_CorC_HlyC_assoc; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the CorC_HlyC domain. CorC_HlyC is a transporter associated domain. This small domain is found in Na+/H+ antiporters, in proteins involved in ...
      pfam01595
      Location:196 → 358
      DUF21; Domain of unknown function DUF21

    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_000002.12 Reference GRCh38.p14 Primary Assembly

      Range
      96760902..96811874
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047443911.1 → XP_047299867.1  metal transporter CNNM4 isoform X1

    2. XM_005263914.5 → XP_005263971.1  metal transporter CNNM4 isoform X2

      Conserved Domains (3) summary
      COG0517
      Location:373 → 500
      CBS; CBS domain [Signal transduction mechanisms]
      cd04590
      Location:382 → 502
      CBS_pair_CorC_HlyC_assoc; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the CorC_HlyC domain. CorC_HlyC is a transporter associated domain. This small domain is found in Na+/H+ antiporters, in proteins involved in ...
      pfam01595
      Location:196 → 358
      DUF21; Domain of unknown function DUF21

    3. XM_047443912.1 → XP_047299868.1  metal transporter CNNM4 isoform X4

    4. XM_005263915.5 → XP_005263972.1  metal transporter CNNM4 isoform X3

      Conserved Domains (3) summary
      COG0517
      Location:373 → 500
      CBS; CBS domain [Signal transduction mechanisms]
      cd04590
      Location:382 → 502
      CBS_pair_CorC_HlyC_assoc; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the CorC_HlyC domain. CorC_HlyC is a transporter associated domain. This small domain is found in Na+/H+ antiporters, in proteins involved in ...
      pfam01595
      Location:196 → 358
      DUF21; Domain of unknown function DUF21

    5. XM_011510956.4 → XP_011509258.1  metal transporter CNNM4 isoform X5

      Conserved Domains (2) summary
      pfam01595
      Location:196 → 358
      DUF21; Domain of unknown function DUF21
      cl15354
      Location:382 → 474
      CBS_pair; The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called ...

    6. XM_017003799.2 → XP_016859288.1  metal transporter CNNM4 isoform X6

    RNA

    1. XR_007071513.1 RNA Sequence

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060926.1 Alternate T2T-CHM13v2.0

      Range
      97267540..97318504
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054341363.1 → XP_054197338.1  metal transporter CNNM4 isoform X1

    2. XM_054341364.1 → XP_054197339.1  metal transporter CNNM4 isoform X2

    3. XM_054341366.1 → XP_054197341.1  metal transporter CNNM4 isoform X4

    4. XM_054341365.1 → XP_054197340.1  metal transporter CNNM4 isoform X3

    5. XM_054341367.1 → XP_054197342.1  metal transporter CNNM4 isoform X5

    6. XM_054341368.1 → XP_054197343.1  metal transporter CNNM4 isoform X6

    RNA

    1. XR_008486323.1 RNA Sequence

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q6P4Q7.3 GenPept UniProtKB/Swiss-Prot:Q6P4Q7

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