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    LEMD3 LEM domain containing 3 [ Homo sapiens (human) ]

    Gene ID: 23592, updated on 3-Nov-2024

    Summary

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    Official Symbol
    LEMD3provided by HGNC
    Official Full Name
    LEM domain containing 3provided by HGNC
    Primary source
    HGNC:HGNC:28887
    See related
    Ensembl:ENSG00000174106 MIM:607844; AllianceGenome:HGNC:28887
    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
    MAN1
    Summary
    This locus encodes a LEM domain-containing protein. The encoded protein functions to antagonize transforming growth factor-beta signaling at the inner nuclear membrane. Two transcript variants encoding different isoforms have been found for this gene. Mutations in this gene have been associated with osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.[provided by RefSeq, Nov 2009]
    Expression
    Ubiquitous expression in testis (RPKM 11.8), bone marrow (RPKM 7.8) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See LEMD3 in Genome Data Viewer
    Location:
    12q14.3
    Exon count:
    13
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 12 NC_000012.12 (65169583..65248355)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 12 NC_060936.1 (65148505..65227374)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 12 NC_000012.11 (65563363..65642135)

    Chromosome 12 - NC_000012.12Genomic Context describing neighboring genes Neighboring gene ATAC-STARR-seq lymphoblastoid active region 6605 Neighboring gene apolipoprotein O pseudogene 3 Neighboring gene uncharacterized LOC124902953 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 6606 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:65563126-65563698 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4630 Neighboring gene ReSE screen-validated silencer GRCh37_chr12:65564244-65564447 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 6608 Neighboring gene Sharpr-MPRA regulatory region 14888 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4631 Neighboring gene MPRA-validated peak1765 silencer Neighboring gene H3K4me1 hESC enhancer GRCh37_chr12:65655701-65656202 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr12:65656203-65656702 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4632 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4633 Neighboring gene methionine sulfoxide reductase B3 Neighboring gene uncharacterized LOC124902954 Neighboring gene keratin 18 pseudogene 60

    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. Intracellular trafficking of MAN1, an integral protein of the nuclear envelope inner membrane. Wu W, et al. J Cell Sci, 2002 Apr 1. PMID 11896184
    2. MAN1, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-beta signaling. Lin F, et al. Hum Mol Genet, 2005 Feb 1. PMID 15601644
    3. LEM domain-containing protein 3 antagonizes TGFβ-SMAD2/3 signaling in a stiffness-dependent manner in both the nucleus and cytosol. Chambers DM, et al. J Biol Chem, 2018 Oct 12. PMID 30108174, Free PMC Article
    4. Germline LEMD3 mutations are rare in sporadic patients with isolated melorheostosis. Hellemans J, et al. Hum Mutat, 2006 Mar. PMID 16470551
    5. The carboxyl-terminal nucleoplasmic region of MAN1 exhibits a DNA binding winged helix domain. Caputo S, et al. J Biol Chem, 2006 Jun 30. PMID 16648637

    See all (115) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Melorheostosis and Osteopoikilosis Clinical and Molecular Description of an Italian Case Series.
      Title: Melorheostosis and Osteopoikilosis Clinical and Molecular Description of an Italian Case Series.
    2. Here we describe the unusual case of a 60-year-old woman with isolated nevus elasticus and a mutation in the LEMD3 (LEM Domain Containing 3) gene.
      Title: Buschke-Ollendorff syndrome due to a novel LEMD3 mutation - an unusual case of alopecia.
    3. analysis of the structural basis for R-SMAD recognition by MAN1 using SMAD2-MAN1 and SMAD1-MAN1 complex structures
      Title: Structural basis for receptor-regulated SMAD recognition by MAN1.
    4. LEMD3 is cleaved by PPM1a into fragments that enter the cytosol to bind SMAD2 and SMAD3, thereby antagonizing signaling initiated by stiffness-triggered activity of TGFbeta.
      Title: LEM domain-containing protein 3 antagonizes TGFβ-SMAD2/3 signaling in a stiffness-dependent manner in both the nucleus and cytosol.
    5. studies demonstrated that lower levels of MAN1 in differentiating MSC are associated with higher osteogenesis and lower adipogenesis. High levels of MAN1 only affected adipogenesis.
      Title: The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation.
    6. LAMD3 Y871X mutation is associated with osteopoikilosis.
      Title: Identification of a novel LEMD3 Y871X mutation in a three-generation family with osteopoikilosis and review of the literature.
    7. Letter/Case-Report: novel frameshift mutation in RNA recognition motif of LEMD3 in patient with Buschke-Ollendorff syndrome.
      Title: RNA recognition motif of LEMD3 as a key player in the pathogenesis of Buschke-Ollendorff syndrome.
    8. A novel mutation in LEMD3 splice site results in Buschke-Ollendorff syndrome.
      Title: Novel Somatic Mutation in LEMD3 Splice Site Results in Buschke-Ollendorff Syndrome with Polyostotic Melorheostosis and Osteopoikilosis.
    9. Data indicate that the inner nuclear membrane protein MAN1 directly binds the transcription activator BMAL1 promoter and enhances its transcription.
      Title: Nuclear envelope protein MAN1 regulates clock through BMAL1.
    10. a nuclear envelope-localized mechanism of inactivating TGF-beta signaling in which MAN1 competes with transcription factors for binding to Smad2 and Smad3 and facilitates their dephosphorylation by PPM1A.
      Title: Inhibition of TGF-β signaling at the nuclear envelope: characterization of interactions between MAN1, Smad2 and Smad3, and PPM1A.
    Submit: New GeneRIF Correction See all GeneRIFs (25)

    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
    Dermatofibrosis lenticularis disseminata
    MedGen: C0265514 OMIM: 166700 GeneReviews: Not available
    		Compare labs

    Copy number response

    Description
    Copy number response
    Triplosensitivity

    No evidence available (Last evaluated 2020-10-19)

    ClinGen Genome Curation Page
    Haploinsufficency

    Sufficient evidence for dosage pathogenicity (Last evaluated 2020-10-19)

    ClinGen Genome Curation PagePubMed

    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 DNA binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables U1 snRNP binding IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in negative regulation of BMP signaling pathway IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in negative regulation of activin receptor signaling pathway IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in negative regulation of transforming growth factor beta receptor signaling pathway IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Component Evidence Code Pubs
    located_in membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in nuclear inner membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in nuclear membrane IDA
    Inferred from Direct Assay
    more info
    		  

    General protein information

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    Preferred Names
    inner nuclear membrane protein Man1
    Names
    LEM domain-containing protein 3
    LEMD3/MKX fusion
    MAN antigen 1
    integral inner nuclear membrane protein

    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_016210.2 RefSeqGene

      Range
      5013..83785
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001167614.2 → NP_001161086.1  inner nuclear membrane protein Man1 isoform 2

      See identical proteins and their annotated locations for NP_001161086.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) uses an alternate in-frame splice site in the 5' coding region, compared to variant 1. This results in a shorter protein (isoform 2), compared to isoform 1.
      Source sequence(s)
      AF112299, AK312473, BX390128
      UniProtKB/Swiss-Prot
      Q9Y2U8
      Conserved Domains (3) summary
      cd12286
      Location:784 → 875
      RRM_Man1; RNA recognition motif in inner nuclear membrane protein Man1 (Man1) and similar proteins
      pfam09402
      Location:535 → 747
      MSC; Man1-Src1p-C-terminal domain
      cl02649
      Location:9 → 51
      LEM; LEM (Lap2/Emerin/Man1) domain found in emerin, lamina-associated polypeptide 2 (LAP2), inner nuclear membrane protein Man1 and similar proteins

    2. NM_014319.5 → NP_055134.2  inner nuclear membrane protein Man1 isoform 1

      See identical proteins and their annotated locations for NP_055134.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).
      Source sequence(s)
      AF112299, AK312473, BX390128
      Consensus CDS
      CCDS8972.1
      UniProtKB/Swiss-Prot
      Q9NT47, Q9NYA5, Q9Y2U8
      Related
      ENSP00000308369.2, ENST00000308330.3
      Conserved Domains (3) summary
      cd12286
      Location:785 → 876
      RRM_Man1; RNA recognition motif in inner nuclear membrane protein Man1 (Man1) and similar proteins
      pfam09402
      Location:538 → 748
      MSC; Man1-Src1p-C-terminal domain
      cl02649
      Location:9 → 51
      LEM; LEM (Lap2/Emerin/Man1) domain found in emerin, lamina-associated polypeptide 2 (LAP2), inner nuclear membrane protein Man1 and similar proteins

    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_000012.12 Reference GRCh38.p14 Primary Assembly

      Range
      65169583..65248355
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060936.1 Alternate T2T-CHM13v2.0

      Range
      65148505..65227374
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q9Y2U8.2 GenPept UniProtKB/Swiss-Prot:Q9Y2U8

    Gene LinkOut

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