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SMPD4 sphingomyelin phosphodiesterase 4 [ Homo sapiens (human) ]

Gene ID: 55627, updated on 7-Apr-2024

Summary

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Official Symbol
SMPD4provided by HGNC
Official Full Name
sphingomyelin phosphodiesterase 4provided by HGNC
Primary source
HGNC:HGNC:32949
See related
Ensembl:ENSG00000136699 MIM:610457; AllianceGenome:HGNC:32949
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
SKNY; NET13; NEDMABA; NEDMEBA; NSMASE3; NSMASE-3
Summary
The protein encoded by this gene is a sphingomyelinase that catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide. This gene is activated by DNA damage, cellular stress, and tumor necrosis factor, but it is downregulated by wild-type p53. The encoded protein localizes to the endoplasmic reticulum and Golgi network. [provided by RefSeq, Mar 2017]
Expression
Ubiquitous expression in bone marrow (RPKM 16.4), testis (RPKM 14.6) and 25 other tissues See more
Orthologs
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Genomic context

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Location:
2q21.1
Exon count:
21
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 2 NC_000002.12 (130151392..130181757, complement)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 2 NC_060926.1 (130585291..130615727, complement)
105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 2 NC_000002.11 (130908965..130939330, complement)

Chromosome 2 - NC_000002.12Genomic Context describing neighboring genes Neighboring gene POTE ankyrin domain family member F Neighboring gene RNA, U6 small nuclear 1049, pseudogene Neighboring gene POTEF antisense RNA 1 Neighboring gene H3K27ac hESC enhancer GRCh37_chr2:130886707-130887281 Neighboring gene mediator complex subunit 15 pseudogene 9 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16521 Neighboring gene coiled-coil domain containing 74B Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16523 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:130917957-130918586 Neighboring gene ReSE screen-validated silencer GRCh37_chr2:130921824-130922007 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:130938087-130938883 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11953 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11954 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:130940784-130941520 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:130941521-130942257 Neighboring gene mitotic spindle organizing protein 2B Neighboring gene tubulin alpha 3e Neighboring gene ras homolog family member Q pseudogene 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
  • 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. Proximity Ligation Mapping of Microcephaly Associated SMPD4 Shows Association with Components of the Nuclear Pore Membrane. Piët ACA, et al. Cells, 2022 Feb 15. PMID 35203325, Free PMC Article
  2. Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis. Magini P, et al. Am J Hum Genet, 2019 Oct 3. PMID 31495489, Free PMC Article
  3. Neutral sphingomyelinase-3 is a DNA damage and nongenotoxic stress-regulated gene that is deregulated in human malignancies. Corcoran CA, et al. Mol Cancer Res, 2008 May. PMID 18505924, Free PMC Article
  4. Neutral sphingomyelinase-3 mediates TNF-stimulated oxidant activity in skeletal muscle. Moylan JS, et al. Redox Biol, 2014. PMID 25180167, Free PMC Article
  5. Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. Ito H, et al. Biochim Biophys Acta, 2009 Nov-Dec. PMID 19698806

See all (67) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. Two novel cases of biallelic SMPD4 variants with brain structural abnormalities.
    Title: Two novel cases of biallelic SMPD4 variants with brain structural abnormalities.
  2. Proximity Ligation Mapping of Microcephaly Associated SMPD4 Shows Association with Components of the Nuclear Pore Membrane.
    Title: Proximity Ligation Mapping of Microcephaly Associated SMPD4 Shows Association with Components of the Nuclear Pore Membrane.
  3. data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the endoplasmic reticulum and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly
    Title: Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.
  4. Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator)
    Title: Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.
  5. Observational study of gene-disease association. (HuGE Navigator)
    Title: Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.
  6. Data show DA remarkably increased the NSMase2 message and protein, whereas little change in NSMase1 and NSMase3 mRNAs.
    Title: Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin.
  7. nSMase3 is an important molecule that is linked to tumorigenesis and cellular stress response
    Title: Neutral sphingomyelinase-3 is a DNA damage and nongenotoxic stress-regulated gene that is deregulated in human malignancies.
Submit: New GeneRIF Correction

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
Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies
MedGen: C5231431 OMIM: 618622 GeneReviews: Not available
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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

HIV-1 interactions

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Protein interactions

Protein Gene Interaction Pubs
Envelope surface glycoprotein gp120 env HIV-1 gp120 binding to CXCR4 induces NADPH oxidase-mediated production of superoxide radicals in neurons, which is involved in the activation of neutral sphingomyelinase PubMed
env In human primary neurons, HIV-1 gp120 induces the activation of sphingomyelinases (primarily neutral sphingomyelinase); antisense knockdown of neutral sphingomyelinase markedly inhibits gp120-mediated apoptosis and cell death of primary neurons PubMed

Go to the HIV-1, Human Interaction Database

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

  • FLJ20297, FLJ20756, KIAA1418

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables metal ion binding IEA
Inferred from Electronic Annotation
more info
  
enables sphingomyelin phosphodiesterase D activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables sphingomyelin phosphodiesterase D activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables sphingomyelin phosphodiesterase activity IEA
Inferred from Electronic Annotation
more info
  
Process Evidence Code Pubs
involved_in cellular response to tumor necrosis factor IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in ceramide biosynthetic process IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in ceramide biosynthetic process IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in endoplasmic reticulum organization IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in glycerophospholipid catabolic process IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in glycerophospholipid catabolic process IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in sphingomyelin catabolic process IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in sphingomyelin catabolic process IDA
Inferred from Direct Assay
more info
 PubMed 
Component Evidence Code Pubs
located_in Golgi apparatus IDA
Inferred from Direct Assay
more info
 PubMed 
located_in Golgi membrane IEA
Inferred from Electronic Annotation
more info
  
located_in endoplasmic reticulum IDA
Inferred from Direct Assay
more info
 PubMed 
located_in endoplasmic reticulum membrane TAS
Traceable Author Statement
more info
  
located_in nuclear envelope ISS
Inferred from Sequence or Structural Similarity
more info
  
located_in nuclear outer membrane IDA
Inferred from Direct Assay
more info
 PubMed 
located_in sarcolemma ISS
Inferred from Sequence or Structural Similarity
more info
  
located_in trans-Golgi network IDA
Inferred from Direct Assay
more info
 PubMed 

General protein information

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Preferred Names
sphingomyelin phosphodiesterase 4
Names
neutral sphingomyelinase 3
neutral sphingomyelinase III
sphingomyelin phosphodiesterase 4, neutral membrane (neutral sphingomyelinase-3)
NP_001164554.1
NP_060221.2
NP_060421.3
XP_011509745.1
XP_011509746.1
XP_024308746.1
XP_047300894.1
XP_054188850.1
XP_054188851.1
XP_054188852.1
XP_054188853.1
XP_054188854.1
XP_054188855.1
XP_054188856.1
XP_054188857.1
XP_054188858.1
XP_054188859.1
XP_054198841.1
XP_054198842.1
XP_054198843.1
XP_054198844.1
XP_054198845.1
XP_054198846.1
XP_054198847.1
XP_054198848.1
XP_054198849.1
XP_054198850.1

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_053070.1 RefSeqGene

    Range
    6149..36343
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_001171083.2 → NP_001164554.1  sphingomyelin phosphodiesterase 4 isoform 3

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) lacks two alternate exons resulting in the loss of an in-frame segment in the 5' coding region, and it also lacks an alternate in-frame exon in the central coding region, compared to variant 2. The resulting isoform (3) is shorter than isoform 2.
    Source sequence(s)
    AC018804, AI393912, AK299185, DA797873
    Consensus CDS
    CCDS54398.1
    UniProtKB/Swiss-Prot
    B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9
    Related
    ENSP00000405187.2, ENST00000431183.6
    Conserved Domains (1) summary
    pfam14724
    Location:47 → 709
    mit_SMPDase; Mitochondrial-associated sphingomyelin phosphodiesterase

  2. NM_017751.4 → NP_060221.2  sphingomyelin phosphodiesterase 4 isoform 1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) lacks an alternate in-frame exon in the central coding region, compared to variant 2, resulting in an isoform (1) that is shorter than isoform 2.
    Source sequence(s)
    AI393912, AK000304, DA797873
    Consensus CDS
    CCDS2156.2
    UniProtKB/Swiss-Prot
    B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9
    Related
    ENSP00000259217.8, ENST00000351288.10
    Conserved Domains (1) summary
    pfam14724
    Location:47 → 782
    mit_SMPDase; Mitochondrial-associated sphingomyelin phosphodiesterase

  3. NM_017951.5 → NP_060421.3  sphingomyelin phosphodiesterase 4 isoform 2

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2) encodes the longest isoform (2).
    Source sequence(s)
    AC018804
    Consensus CDS
    CCDS42751.2
    UniProtKB/Swiss-Prot
    B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9
    UniProtKB/TrEMBL
    A0A7P0TB24
    Related
    ENSP00000506463.1, ENST00000680298.1
    Conserved Domains (1) summary
    pfam14724
    Location:8 → 772
    mit_SMPDase; Mitochondrial-associated sphingomyelin phosphodiesterase

RNA

  1. NR_033231.3 RNA Sequence

    Status: REVIEWED

    Description
    Transcript Variant: This variant (5) lacks an alternate internal exon in the 5' region, compared to variant 2. This variant is represented as non-coding because the use of the supported translational start codon, as used in variant 2, renders the transcript a candidate for nonsense-mediated mRNA decay (NMD).
    Source sequence(s)
    AC018804, AI393912, BC064947, DA797873
    Related
    ENST00000454468.5

  2. NR_033232.3 RNA Sequence

    Status: REVIEWED

    Description
    Transcript Variant: This variant (6) lacks an alternate internal exon in both the 5' and central regions, compared to variant 2. This variant is represented as non-coding because the use of the supported translational start codon, as used in variant 2, renders the transcript a candidate for nonsense-mediated mRNA decay (NMD).
    Source sequence(s)
    AC018804, AI393912, AK303519, DA797873
    Related
    ENST00000412570.5

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
    130151392..130181757 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_011511444.4 → XP_011509746.1  sphingomyelin phosphodiesterase 4 isoform X2

    UniProtKB/Swiss-Prot
    B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9
    Conserved Domains (1) summary
    pfam14724
    Location:125 → 860
    mit_SMPDase; Mitochondrial-associated sphingomyelin phosphodiesterase

  2. XM_011511443.3 → XP_011509745.1  sphingomyelin phosphodiesterase 4 isoform X1

    UniProtKB/Swiss-Prot
    B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9
    Conserved Domains (1) summary
    pfam14724
    Location:125 → 889
    mit_SMPDase; Mitochondrial-associated sphingomyelin phosphodiesterase

  3. XM_047444938.1 → XP_047300894.1  sphingomyelin phosphodiesterase 4 isoform X3

    Related
    ENSP00000401648.1, ENST00000439886.5

  4. XM_024452978.2 → XP_024308746.1  sphingomyelin phosphodiesterase 4 isoform X4

    Conserved Domains (1) summary
    pfam14724
    Location:97 → 552
    mit_SMPDase; Mitochondrial-associated sphingomyelin phosphodiesterase

Reference GRCh38.p14 PATCHES

Genomic

  1. NW_025791762.1 Reference GRCh38.p14 PATCHES

    Range
    327940..358309 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054332880.1 → XP_054188855.1  sphingomyelin phosphodiesterase 4 isoform X8

  2. XM_054332879.1 → XP_054188854.1  sphingomyelin phosphodiesterase 4 isoform X7

  3. XM_054332878.1 → XP_054188853.1  sphingomyelin phosphodiesterase 4 isoform X2

  4. XM_054332876.1 → XP_054188851.1  sphingomyelin phosphodiesterase 4 isoform X6

  5. XM_054332877.1 → XP_054188852.1  sphingomyelin phosphodiesterase 4 isoform X1

  6. XM_054332875.1 → XP_054188850.1  sphingomyelin phosphodiesterase 4 isoform X5

  7. XM_054332881.1 → XP_054188856.1  sphingomyelin phosphodiesterase 4 isoform X9

  8. XM_054332883.1 → XP_054188858.1  sphingomyelin phosphodiesterase 4 isoform X4

  9. XM_054332882.1 → XP_054188857.1  sphingomyelin phosphodiesterase 4 isoform X10

  10. XM_054332884.1 → XP_054188859.1  sphingomyelin phosphodiesterase 4 isoform X11

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060926.1 Alternate T2T-CHM13v2.0

    Range
    130585291..130615727 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054342867.1 → XP_054198842.1  sphingomyelin phosphodiesterase 4 isoform X13

  2. XM_054342866.1 → XP_054198841.1  sphingomyelin phosphodiesterase 4 isoform X12

  3. XM_054342869.1 → XP_054198844.1  sphingomyelin phosphodiesterase 4 isoform X2

  4. XM_054342868.1 → XP_054198843.1  sphingomyelin phosphodiesterase 4 isoform X1

  5. XM_054342871.1 → XP_054198846.1  sphingomyelin phosphodiesterase 4 isoform X15

  6. XM_054342870.1 → XP_054198845.1  sphingomyelin phosphodiesterase 4 isoform X14

  7. XM_054342872.1 → XP_054198847.1  sphingomyelin phosphodiesterase 4 isoform X16

  8. XM_054342874.1 → XP_054198849.1  sphingomyelin phosphodiesterase 4 isoform X4

  9. XM_054342873.1 → XP_054198848.1  sphingomyelin phosphodiesterase 4 isoform X17

  10. XM_054342875.1 → XP_054198850.1  sphingomyelin phosphodiesterase 4 isoform X18

Suppressed Reference Sequence(s)

The following Reference Sequences have been suppressed. Explain

  1. NM_001171084.1: Suppressed sequence

    Description
    NM_001171084.1: This RefSeq was permanently suppressed because currently there is insufficient support for the transcript and the protein.
Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
Q9NXE4.3 GenPept UniProtKB/Swiss-Prot:Q9NXE4

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