Atlas of Genetics and Cytogenetics in Oncology and Haematology


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GLMN (Glomulin)

Identity

Other namesGLMN
FAP68
FAP48
HGNC (Hugo) GLMN
LocusID (NCBI) 11146
Location 1p22.1
Location_base_pair Starts at 92711955 and ends at 92764566 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Note The gene was identified by linkage mapping and positional cloning. There is no evidence for locus heterogeneity. Haplotype sharing has been reported for an important number of families.

DNA/RNA

Description The genomic DNA of the glomulin gene spans about 55 kbp and contains 19 exons coding for 1785 bp. The first exon is non coding, the start codon is located on the second exon and the stop codon in the last exon.
Transcription In all human and murine tissues tested, a about 2 kb transcript was observed by Northern blot hybridization, suggesting that glomulin expression is ubiquitous. This could be due to the presence of glomulin-expressing blood vessels in the various tissues analysed.
By in situ hybridisation on murine embryos, glomulin expression was evident at embryonic E10.5 days post-coitum (dpc) and localized to the cardiac outflow tract. Between E11.5 to 14.5 dpc, glomulin mRNA is most abundant in the walls of large vessels (e.g. dorsal aorta). At E14.5 dpc, E16.5 dpc, and in adult tissues, expression of glomulin is clearly restricted to vascular smooth muscle cells. The high level of glomulin expression in the murine vasculature indicates that glomulin may have an important role in blood vessel development and/or maintenance.
A truncated form of glomulin, called FAP48, with an altered carboxy-terminal end, was isolated from a Jurkat-cell library. However FAP48, which presents 70% homology with glomulin, was not detected in other tissues and cells tested. Thus, it might be an aberrant transcript in this library.
Pseudogene In man, no paralogue exists. Yet, a pseudogene is located on chromosome 21. It contains only a few exons (exons 6 to 10), without intervening introns and with several nucleotide differences. Thus, glomulin seems to be unique in the human genome.

Protein

Note Glomulin was identified by reverse genetics, and its function is currently unknown.
Description Glomulin gene encodes a protein of 594 amino acids (68 kDa). In silico analysis reveals no known functional or structural domains, but a few potential phosphorylation and glycosylation sites.
Expression (see above, para Transcription)
Localisation By in silico analysis, no signal sequence or clear transmembrane domain in glomulin has been identified. Glomulin (FAP68) is likely an intracellular protein.
Function The exact function of glomulin is unknown.
Glomulin (under the name of FAP48) has been described to interact with FKBP12, an immunophilin that binds the immunosuppressive drugs FK506 and rapamycin. FKBP12 interacts with the TGFbeta type I receptor, and prevents its phosphorylation by the type II receptor in the absence of TGFbeta. Thus, FKBP12 safeguards against the ligand-independent activation of this pathway. Glomulin, through its interaction with FKBP12, could act as a repressor of this inhibition.
Glomulin has also been described to interact with the last 30 amino acids of the C-terminal part of the HGF receptor, c-MET. This receptor is a transmembrane tyrosine kinase, which becomes tyrosine-phosphorylated upon activation by HGF. Glomulin interacts with the inactive, non phosphorylated form of c-MET. When c-MET is activated by HGF, glomulin is released in a phosphorylated form. This leads to p70 S6 protein kinase (p70S6K) phosphorylation. This activation occurs synergistically with the activation by the c-MET-activated PI3 kinase. It is not known whether glomulin activates p70S6K directly or indirectly. The p70S6K is a key regulator of protein synthesis. Glomulin could thereby control cellular events such as migration and cell division.
The third reported glomulin partner is Cul7, a Cul1 homologue. This places glomulin in an SCF-like complex, which is implicated in protein ubiquitination and degradation.
Homology Glomulin seems to be an unique protein. No paralogue has been found and its lack in GVM is not compensated by another protein. Orthologues of glomulin have been identified in other species (cat, chimpanzee, cow, dog, mouse, rat, rhesus macaque, xenopus, zebrafish) and thus it is present in all vertebrates but not in insects or bacteries.

Mutations

Note There is no phenotype-genotype correlation in GVM.
 
  Schematic representation of glomulin : The two stars (*) indicate the start and the stop codons, in exon 2 and 19 respectively. All known mutations are shown. Somatic second hit is in blue.
Germinal To date, 29 different inherited mutations (deletions, insertions and nonsense substitutions) have been identified. The most 5' mutation are located in the first coding exon. The majority of them cause premature truncation of the protein and likely result in loss-of-function. One mutation deletes 3 nucleotides resulting in the deletion of an asparagine at position 394 of the protein.
More than 70% of GVMs are caused by eight different mutations in glomulin: 157delAAGAA (40,7%), 108C>A (9,3%), 1179delCAA (8,1%), 421insT and 738insT (4,65% each), 554delA+556delCCT (3,5%), 107insG and IVS5-1(G>A) (2,3% each).
Somatic The phenotypic variability observed in GVM could be explained by the need of a somatic second-hit mutation. Such a mechanism was discovered in one GVM (somatic mutation 980delCAGAA), suggesting that the lesion is due to a complete localized loss-of-function of glomulin. This concept can explain why some patients have bigger lesions than others, why new lesions appear, and why they are multifocal. This could also explain, why some mutation carriers are unaffected.

Implicated in

Entity Glomuvenous malformation (GVM)
Note GVM is often, if not always, hereditary, and transmitted as an autosomal dominant disorder.
Disease GVM is a localized bluish-purple cutaneous vascular lesion, histologically consisting of distended venous channels with flattened endothelium surrounded by variable number of maldifferentiated smooth muscle-like "glomus cells" in the wall. GVM account for 5% of venous anomalies referred to centers for vascular anomalies.
Seven features characterize GVM lesions : (1) Colour: GVMs can be pink in infants, the most are bluish-purple; (2) Affected tissues: the lesions are localized to the skin and subcutis; (3) Localization: lesions are more often located on the extremities; (4) Appearance : lesions are usually nodular and multifocal. They are often hyperkeratotic; (5) The lesions are not compressible; The lesions are painful on palpation; (7) New lesions can appear with time, likely after trauma
GVM has no neoplastic histological characteristics and never becomes malignant.
  

External links

Nomenclature
HGNC (Hugo)GLMN   14373
Cards
AtlasGLMNID43022ch1p22
Entrez_Gene (NCBI)GLMN  11146  glomulin, FKBP associated protein
GeneCards (Weizmann)GLMN
Ensembl (Hinxton)ENSG00000174842 [Gene_View]  chr1:92711955-92764566 [Contig_View]  GLMN [Vega]
ICGC DataPortalENSG00000174842
cBioPortalGLMN
AceView (NCBI)GLMN
Genatlas (Paris)GLMN
WikiGenes11146
SOURCE (Princeton)NM_007070 NM_053274
Genomic and cartography
GoldenPath (UCSC)GLMN  -  1p22.1   chr1:92711955-92764566 -  1p22.1   [Description]    (hg19-Feb_2009)
EnsemblGLMN - 1p22.1 [CytoView]
Mapping of homologs : NCBIGLMN [Mapview]
OMIM138000   601749   
Gene and transcription
Genbank (Entrez)AJ302735 AJ347709 AK295971 BC001257 BG187128
RefSeq transcript (Entrez)NM_007070 NM_053274
RefSeq genomic (Entrez)AC_000133 NC_000001 NC_018912 NG_009796 NT_032977 NW_001838589 NW_004929290
Consensus coding sequences : CCDS (NCBI)GLMN
Cluster EST : UnigeneHs.49105 [ NCBI ]
CGAP (NCI)Hs.49105
Alternative Splicing : Fast-db (Paris)GSHG0002260
Alternative Splicing GalleryENSG00000174842
Gene ExpressionGLMN [ NCBI-GEO ]     GLMN [ SEEK ]   GLMN [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ92990 (Uniprot)
NextProtQ92990  [Medical]
With graphics : InterProQ92990
Splice isoforms : SwissVarQ92990 (Swissvar)
Domains : Interpro (EBI)Glomulin/ALF4 [organisation]   YAP-bd/ALF4/Glomulin [organisation]  
Related proteins : CluSTrQ92990
Domain families : Pfam (Sanger)Kinetochor_Ybp2 (PF08568)   
Domain families : Pfam (NCBI)pfam08568   
DMDM Disease mutations11146
Blocks (Seattle)Q92990
PDB (SRS)4F52   
PDB (PDBSum)4F52   
PDB (IMB)4F52   
PDB (RSDB)4F52   
Human Protein AtlasENSG00000174842 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ92990
HPRD03451
IPIIPI00074604   IPI00218838   IPI01015383   
Protein Interaction databases
DIP (DOE-UCLA)Q92990
IntAct (EBI)Q92990
FunCoupENSG00000174842
BioGRIDGLMN
InParanoidQ92990
Interologous Interaction database Q92990
IntegromeDBGLMN
STRING (EMBL)GLMN
Ontologies - Pathways
Ontology : AmiGOvasculogenesis  neural tube closure  hepatocyte growth factor receptor binding  protein binding  intracellular  negative regulation of protein ubiquitination  cullin-RING ubiquitin ligase complex  Cul2-RING ubiquitin ligase complex  Cul3-RING ubiquitin ligase complex  Cul4A-RING E3 ubiquitin ligase complex  ubiquitin protein ligase binding  regulation of proteasomal ubiquitin-dependent protein catabolic process  regulation of gene expression, epigenetic  negative regulation of T cell proliferation  positive regulation of phosphorylation  muscle cell differentiation  positive regulation of interleukin-2 biosynthetic process  positive regulation of cytokine secretion  ubiquitin-protein transferase inhibitor activity  
Ontology : EGO-EBIvasculogenesis  neural tube closure  hepatocyte growth factor receptor binding  protein binding  intracellular  negative regulation of protein ubiquitination  cullin-RING ubiquitin ligase complex  Cul2-RING ubiquitin ligase complex  Cul3-RING ubiquitin ligase complex  Cul4A-RING E3 ubiquitin ligase complex  ubiquitin protein ligase binding  regulation of proteasomal ubiquitin-dependent protein catabolic process  regulation of gene expression, epigenetic  negative regulation of T cell proliferation  positive regulation of phosphorylation  muscle cell differentiation  positive regulation of interleukin-2 biosynthetic process  positive regulation of cytokine secretion  ubiquitin-protein transferase inhibitor activity  
Protein Interaction DatabaseGLMN
Wikipedia pathwaysGLMN
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)GLMN
snp3D : Map Gene to Disease11146
SNP (GeneSNP Utah)GLMN
SNP : HGBaseGLMN
Genetic variants : HAPMAPGLMN
Exome VariantGLMN
1000_GenomesGLMN 
ICGC programENSG00000174842 
Somatic Mutations in Cancer : COSMICGLMN 
CONAN: Copy Number AnalysisGLMN 
Mutations and Diseases : HGMDGLMN
Mutations and Diseases : intOGenGLMN
Genomic VariantsGLMN  GLMN [DGVbeta]
dbVarGLMN
ClinVarGLMN
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM138000    601749   
MedgenGLMN
GENETestsGLMN
Disease Genetic AssociationGLMN
Huge Navigator GLMN [HugePedia]  GLMN [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneGLMN
Homology/Alignments : Family Browser (UCSC)GLMN
Phylogenetic Trees/Animal Genes : TreeFamGLMN
Chemical/Protein Interactions : CTD11146
Chemical/Pharm GKB GenePA134870088
Clinical trialGLMN
Cancer Resource (Charite)ENSG00000174842
Other databases
Probes
Litterature
PubMed28 Pubmed reference(s) in Entrez
CoreMineGLMN
iHOPGLMN
OncoSearchGLMN

Bibliography

Multiple glomus tumors. A clinical and electron microscopic study.
Goodman TF, Abele DC
Archives of dermatology. 1971 ; 103 (1) : 11-23.
PMID 4321799
 
FAP48, a new protein that forms specific complexes with both immunophilins FKBP59 and FKBP12. Prevention by the immunosuppressant drugs FK506 and rapamycin.
Chambraud B, Radanyi C, Camonis JH, Shazand K, Rajkowski K, Baulieu EE
The Journal of biological chemistry. 1996 ; 271 (51) : 32923-32929.
PMID 8955134
 
Mechanism of TGFbeta receptor inhibition by FKBP12.
Chen YG, Liu F, Massague J
The EMBO journal. 1997 ; 16 (13) : 3866-3876.
PMID 9233797
 
A gene for inherited cutaneous venous anomalies (glomangiomas) localizes to chromosome 1p21-22.
Boon LM, Brouillard P, Irrthum A, Karttunen L, Warman ML, Rudolph R, Mulliken JB, Olsen BR, Vikkula M
American journal of human genetics. 1999 ; 65 (1) : 125-133.
PMID 10364524
 
High-resolution physical and transcript map of the locus for venous malformations with glomus cells (VMGLOM) on chromosome 1p21-p22.
Brouillard P, Olsen BR, Vikkula M
Genomics. 2000 ; 67 (1) : 96-101.
PMID 10945476
 
Ligand-regulated binding of FAP68 to the hepatocyte growth factor receptor.
Grisendi S, Chambraud B, Gout I, Comoglio PM, Crepaldi T
The Journal of biological chemistry. 2001 ; 276 (49) : 46632-46638.
PMID 11571281
 
Linkage disequilibrium narrows locus for venous malformation with glomus cells (VMGLOM) to a single 1.48 Mbp YAC.
Irrthum A, Brouillard P, Enjolras O, Gibbs NF, Eichenfield LF, Olsen BR, Mulliken JB, Boon LM, Vikkula M
European journal of human genetics : EJHG. 2001 ; 9 (1) : 34-38.
PMID 11175297
 
Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (glomangiomas).
Brouillard P, Boon LM, Mulliken JB, Enjolras O, Ghassibˆ© M, Warman ML, Tan OT, Olsen BR, Vikkula M
American journal of human genetics. 2002 ; 70 (4) : 866-874.
PMID 11845407
 
Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis.
Arai T, Kasper JS, Skaar JR, Ali SH, Takahashi C, DeCaprio JA
Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (17) : 9855-9860.
PMID 12904573
 
Glomuvenous malformation (glomangioma) and venous malformation: distinct clinicopathologic and genetic entities.
Boon LM, Mulliken JB, Enjolras O, Vikkula M
Archives of dermatology. 2004 ; 140 (8) : 971-976.
PMID 15313813
 
Glomulin is predominantly expressed in vascular smooth muscle cells in the embryonic and adult mouse.
McIntyre BA, Brouillard P, Aerts V, Gutierrez-Roelens I, Vikkula M
Gene expression patterns : GEP. 2004 ; 4 (3) : 351-358.
PMID 15053987
 
Four common glomulin mutations cause two thirds of glomuvenous malformations (familial glomangiomas): evidence for a founder effect.
Brouillard P, Ghassibˆ© M, Penington A, Boon LM, Dompmartin A, Temple IK, Cordisco M, Adams D, Piette F, Harper JI, Syed S, Boralevi F, TaˆØeb A, Danda S, Baselga E, Enjolras O, Mulliken JB, Vikkula M
Journal of medical genetics. 2005 ; 42 (2) : page e13.
PMID 15689436
 
[Medical and surgical treatment of venous malformations]
Boon LM, Vanwijck R
Annales de chirurgie plastique et esthetique. 2006 ; 51 (4-5) : 403-411.
PMID 17005307
 
Congenital plaque-type glomuvenous malformations presenting in childhood.
Mallory SB, Enjolras O, Boon LM, Rogers E, Berk DR, Blei F, Baselga E, Ros AM, Vikkula M
Archives of dermatology. 2006 ; 142 (7) : 892-896.
PMID 16847206
 
GLMN and Glomuvenous Malformation.
Brouillard P, Enjolras O, Boon LM, Vikkula M
Inborn Errors of Development 2e, edited by Charles Epstein, Robert Erickson and Anthony Wynshaw..
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written07-2007Virginie Aerts, Pascal Brouillard, Laurence M. Boon, Miikka Vikkula
Human Molecular Genetics (GEHU) de Duve Institute, Universite catholique de Louvain, Avenue Hippocrate 74(+5), bp. 75.39, B-1200 Brussels, Belgium

Citation

This paper should be referenced as such :
Aerts, V ; Brouillard, P ; Boon, LM ; Vikkula, M
GLMN (glomulin)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(1):41-43.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/GLMNID43022ch1p22.html

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indexed on : Tue Aug 26 15:28:10 CEST 2014

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