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Taking over the Atlas
Dear Colleagues,
The Atlas, once more, is in great danger, and I will have to proceed to a collective economic lay-off of all the team involved in the Atlas before the begining of April 2015 (a foundation having suddenly withdrawn its commitment to support the Atlas). I ask you herein if any Scientific Society (a Society of Cytogenetics, of Clinical Genetics, of Hematology, or a Cancer Society, or any other...), any University and/or Hospital, any Charity, or any database would be interested in taking over the Atlas, in whole or in part. If taking charge of the whole lot is too big, a consortium of various actors could be the solution (I am myself trying to find partners). Could you please spread the information, contact the relevant authorities, and find partners.
Survival of the Atlas will be critically dependant upon your ability to find solutions (and urgently!).
Kind regards.
Jean-Loup Huret jlhuret@AtlasGeneticsOncology.org
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PLAGL1 (Pleomorphic adenoma gene-like 1)

Identity

Other namesDKFZp781P1017
LOT1
MGC126275
MGC126276
ZAC
ZAC1
HGNC (Hugo) PLAGL1
LocusID (NCBI) 5325
Location 6q24.2
Location_base_pair Starts at 144261437 and ends at 144385735 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
  Schematic view of the PLAGL1 gene. A. The six exons, shown in red, are 326; 72; 1443; 75; 475; 2380 bp, respectively. The introns are approximately 39; 2.6; 4.2; 12.5; 5.5 kbp in size, respectively. B. The figure shows three splice variants of PLAGL1; the exons are shown as a box.
Description The genome is about 64 kbp with six exons and five introns. The major mRNA transcript is about 4.7 kb in size.
Transcription At least three splicing variants (See Figure, above)

Protein

Description The PLAGL1 protein is a seven C2H2-type zinc finger protein. The seven zinc finger domain is located at the amino terminal region, from the amino acid residue 1 to 210. Additional features of note are proline and glutamine rich regions at the carboxyl terminal portion (residues 220 to 444). There are two nuclear localization signals at the amino terminal region.
Expression Ovary, breast, brain, liver, spleen, thymus, prostate, uterus, testis, intestine, colon, leukocytes.
Localisation Nuclear
Function The PLAGL1 protein is a candidate tumor suppressor gene and has been shown to have transactivation and DNA-binding activity and to exhibit antiproliferative activities.
Homology Homologous to the mouse and Rat plagl1 and to the human PLAG1 and PLAGL2 proteins.

Mutations

Note Mutation has not been found in the PLAGL1 coding region.

Implicated in

Entity Carcinogenicity
Note Alteration of the gene expression was found to be a potential genetic event silencing the PLAGL1 gene in cancers such as breast primary tumors, ovarian primary tumors and tumor-derived cell lines, basal cell carcinoma, head and neck squamous cell carcinoma (HNSCC), and extraskeletal myxoid chondrosarcoma (EMC). Several mechanisms have been shown to regulate the PLAGL1 gene expression, including growth factor receptor activation, epigenetic factors, maternal imprinting, and loss of heterozygosity (LOH). Allelic deletion of 6q24-q25, the PLAGL1 locus, in the tumor tissues has been shown in the cancers of ovarian, breast, HNSCC, and pheochromocytomas (PCCs).
Disease Cancer
  
Entity Transient Neonatal Diabetes (TNDM)
Note Initial reports suggested that transient neonatal diabetes mellitus (TNDM), a rare condition characterized in the patients by intrauterine growth retardation, dehydration, failure to thrive, and hyperglycemia due to a lack of normal insulin secretion, is associated with paternal uniparental disomy (UPD) of chromosome 6 (UPD 6). Later studies showed the involvement of an imprinted gene in this disease within the chromosomal region 6q24.1-q24.3 between markers D6S1699 and D6S1010. Analysis of the CpG islands in the TNDM critical region, using DNA from TNDM patients with paternal UPD 6 and normal controls, suggested PLAGL1/LOT1/ZAC1 as a candidate imprinted gene for this disease.
Disease Diabetes mellitus
  

To be noted

PLAGL1 has been implicated in embryonic development. The gene is variably expressed in different tissues and stages during development. Inactivation of this maternally repressed gene resulted in intrauterine growth restriction, altered bone formation, and neonatal lethality.

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors AmeloblastomID5945

External links

Nomenclature
HGNC (Hugo)PLAGL1   9046
Cards
AtlasPLAGL1ID41737ch6q24
Entrez_Gene (NCBI)PLAGL1  5325  pleiomorphic adenoma gene-like 1
GeneCards (Weizmann)PLAGL1
Ensembl hg19 (Hinxton)ENSG00000118495 [Gene_View]  chr6:144261437-144385735 [Contig_View]  PLAGL1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000118495 [Gene_View]  chr6:144261437-144385735 [Contig_View]  PLAGL1 [Vega]
ICGC DataPortalENSG00000118495
cBioPortalPLAGL1
AceView (NCBI)PLAGL1
Genatlas (Paris)PLAGL1
WikiGenes5325
SOURCE (Princeton)PLAGL1
Genomic and cartography
GoldenPath hg19 (UCSC)PLAGL1  -     chr6:144261437-144385735 -  6q24-q25   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)PLAGL1  -     6q24-q25   [Description]    (hg38-Dec_2013)
EnsemblPLAGL1 - 6q24-q25 [CytoView hg19]  PLAGL1 - 6q24-q25 [CytoView hg38]
Mapping of homologs : NCBIPLAGL1 [Mapview hg19]  PLAGL1 [Mapview hg38]
OMIM601410   603044   
Gene and transcription
Genbank (Entrez)AI741398 AJ006354 AJ303119 AJ311395 AK091707
RefSeq transcript (Entrez)NM_001080951 NM_001080952 NM_001080953 NM_001080954 NM_001080955 NM_001080956 NM_001289037 NM_001289038 NM_001289039 NM_001289040 NM_001289041 NM_001289042 NM_001289043 NM_001289044 NM_001289045 NM_001289046 NM_001289047 NM_001289048 NM_001289049 NM_002656 NM_006718
RefSeq genomic (Entrez)AC_000138 NC_000006 NC_018917 NG_009384 NT_025741 NW_001838990 NW_004929328
Consensus coding sequences : CCDS (NCBI)PLAGL1
Cluster EST : UnigeneHs.743225 [ NCBI ]
CGAP (NCI)Hs.743225
Alternative Splicing : Fast-db (Paris)GSHG0026971
Alternative Splicing GalleryENSG00000118495
Gene ExpressionPLAGL1 [ NCBI-GEO ]     PLAGL1 [ SEEK ]   PLAGL1 [ MEM ]
SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UM63 (Uniprot)
NextProtQ9UM63  [Medical]
With graphics : InterProQ9UM63
Splice isoforms : SwissVarQ9UM63 (Swissvar)
Domaine pattern : Prosite (Expaxy)ZINC_FINGER_C2H2_1 (PS00028)    ZINC_FINGER_C2H2_2 (PS50157)   
Domains : Interpro (EBI)C2H2_Znf_fam    PLAGL1    Znf_C2H2    Znf_C2H2-like    Znf_C2H2/integrase_DNA-bd   
Related proteins : CluSTrQ9UM63
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Domain families : Smart (EMBL)ZnF_C2H2 (SM00355)  
DMDM Disease mutations5325
Blocks (Seattle)Q9UM63
Human Protein AtlasENSG00000118495
Peptide AtlasQ9UM63
HPRD16010
IPIIPI00645881   IPI00220818   IPI01009516   IPI00375897   
Protein Interaction databases
DIP (DOE-UCLA)Q9UM63
IntAct (EBI)Q9UM63
FunCoupENSG00000118495
BioGRIDPLAGL1
IntegromeDBPLAGL1
STRING (EMBL)PLAGL1
Ontologies - Pathways
QuickGOQ9UM63
Ontology : AmiGORNA polymerase II regulatory region sequence-specific DNA binding  sequence-specific DNA binding RNA polymerase II transcription factor activity  RNA polymerase II transcription regulatory region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription  DNA binding  nucleus  nucleus  nucleolus  cytoplasm  Golgi apparatus  transcription from RNA polymerase II promoter  apoptotic process  cell cycle arrest  cell differentiation  skeletal muscle cell differentiation  positive regulation of transcription from RNA polymerase II promoter  metal ion binding  
Ontology : EGO-EBIRNA polymerase II regulatory region sequence-specific DNA binding  sequence-specific DNA binding RNA polymerase II transcription factor activity  RNA polymerase II transcription regulatory region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription  DNA binding  nucleus  nucleus  nucleolus  cytoplasm  Golgi apparatus  transcription from RNA polymerase II promoter  apoptotic process  cell cycle arrest  cell differentiation  skeletal muscle cell differentiation  positive regulation of transcription from RNA polymerase II promoter  metal ion binding  
Protein Interaction DatabasePLAGL1
DoCM (Curated mutations)PLAGL1
Wikipedia pathwaysPLAGL1
Gene fusion - rearrangements
Polymorphisms : SNP, variants
NCBI Variation ViewerPLAGL1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PLAGL1
dbVarPLAGL1
ClinVarPLAGL1
1000_GenomesPLAGL1 
Exome Variant ServerPLAGL1
SNP (GeneSNP Utah)PLAGL1
SNP : HGBasePLAGL1
Genetic variants : HAPMAPPLAGL1
Genomic Variants (DGV)PLAGL1 [DGVbeta]
Mutations
ICGC Data PortalENSG00000118495 
Somatic Mutations in Cancer : COSMICPLAGL1 
CONAN: Copy Number AnalysisPLAGL1 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)6:144261437-144385735
Mutations and Diseases : HGMDPLAGL1
OMIM601410    603044   
MedgenPLAGL1
NextProtQ9UM63 [Medical]
GENETestsPLAGL1
Disease Genetic AssociationPLAGL1
Huge Navigator PLAGL1 [HugePedia]  PLAGL1 [HugeCancerGEM]
snp3D : Map Gene to Disease5325
DGIdb (Drug Gene Interaction db)PLAGL1
General knowledge
Homologs : HomoloGenePLAGL1
Homology/Alignments : Family Browser (UCSC)PLAGL1
Phylogenetic Trees/Animal Genes : TreeFamPLAGL1
Chemical/Protein Interactions : CTD5325
Chemical/Pharm GKB GenePA33379
Clinical trialPLAGL1
Cancer Resource (Charite)ENSG00000118495
Other databases
Probes
Litterature
PubMed54 Pubmed reference(s) in Entrez
CoreMinePLAGL1
GoPubMedPLAGL1
iHOPPLAGL1

Bibliography

Identification of a zinc-finger gene at 6q25: a chromosomal region implicated in development of many solid tumors.
Abdollahi A, Roberts D, Godwin AK, Schultz DC, Sonoda G, Testa JR, Hamilton TC
Oncogene. 1997 ; 14 (16) : 1973-1979.
PMID 9150364
 
Identification of a gene containing zinc-finger motifs based on lost expression in malignantly transformed rat ovarian surface epithelial cells.
Abdollahi A, Godwin AK, Miller PD, Getts LA, Schultz DC, Taguchi T, Testa JR, Hamilton TC
Cancer research. 1997 ; 57 (10) : 2029-2034.
PMID 9158001
 
Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain.
Spengler D, Villalba M, Hoffmann A, Pantaloni C, Houssami S, Bockaert J, Journot L
The EMBO journal. 1997 ; 16 (10) : 2814-2825.
PMID 9184226
 
Delayed up-regulation of Zac1 and PACAP type I receptor after transient focal cerebral ischemia in mice.
Gillardon F, Hata R, Hossmann KA
Brain research. Molecular brain research. 1998 ; 61 (1-2) : 207-210.
PMID 9795221
 
Transcriptional activation capacity of the novel PLAG family of zinc finger proteins.
Kas K, Voz ML, Hensen K, Meyen E, Van de Ven WJ
The Journal of biological chemistry. 1998 ; 273 (36) : 23026-23032.
PMID 9722527
 
hZAC encodes a zinc finger protein with antiproliferative properties and maps to a chromosomal region frequently lost in cancer.
Varrault A, Ciani E, Apiou F, Bilanges B, Hoffmann A, Pantaloni C, Bockaert J, Spengler D, Journot L
Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (15) : 8835-8840.
PMID 9671765
 
LOT1 is a growth suppressor gene down-regulated by the epidermal growth factor receptor ligands and encodes a nuclear zinc-finger protein.
Abdollahi A, Bao R, Hamilton TC
Oncogene. 1999 ; 18 (47) : 6477-6487.
PMID 10597250
 
Loss of expression of the candidate tumor suppressor gene ZAC in breast cancer cell lines and primary tumors.
Bilanges B, Varrault A, Basyuk E, Rodriguez C, Mazumdar A, Pantaloni C, Bockaert J, Theillet C, Spengler D, Journot L
Oncogene. 1999 ; 18 (27) : 3979-3988.
PMID 10435621
 
Inhibition of Zac1, a new gene differentially expressed in the anterior pituitary, increases cell proliferation.
Pagotto U, Arzberger T, Ciani E, Lezoualc'h F, Pilon C, Journot L, Spengler D, Stalla GK
Endocrinology. 1999 ; 140 (2) : 987-996.
PMID 9927333
 
A novel imprinted gene, HYMAI, is located within an imprinted domain on human chromosome 6 containing ZAC.
Arima T, Drewell RA, Oshimura M, Wake N, Surani MA
Genomics. 2000 ; 67 (3) : 248-255.
PMID 10936046
 
Mouse Zac1, a transcriptional coactivator and repressor for nuclear receptors.
Huang SM, Stallcup MR
Molecular and cellular biology. 2000 ; 20 (5) : 1855-1867.
PMID 10669760
 
The cell cycle control gene ZAC/PLAGL1 is imprinted--a strong candidate gene for transient neonatal diabetes.
Kamiya M, Judson H, Okazaki Y, Kusakabe M, Muramatsu M, Takada S, Takagi N, Arima T, Wake N, Kamimura K, Satomura K, Hermann R, Bonthron DT, Hayashizaki Y
Human molecular genetics. 2000 ; 9 (3) : 453-460.
PMID 10655556
 
The expression of the antiproliferative gene ZAC is lost or highly reduced in nonfunctioning pituitary adenomas.
Pagotto U, Arzberger T, Theodoropoulou M, Grˆşbler Y, Pantaloni C, Saeger W, Losa M, Journot L, Stalla GK, Spengler D
Cancer research. 2000 ; 60 (24) : 6794-6799.
PMID 11156367
 
Zac1 (Lot1), a potential tumor suppressor gene, and the gene for epsilon-sarcoglycan are maternally imprinted genes: identification by a subtractive screen of novel uniparental fibroblast lines.
Piras G, El Kharroubi A, Kozlov S, Escalante-Alcalde D, Hernandez L, Copeland NG, Gilbert DJ, Jenkins NA, Stewart CL
Molecular and cellular biology. 2000 ; 20 (9) : 3308-3315.
PMID 10757814
 
Alternative splicing of the imprinted candidate tumor suppressor gene ZAC regulates its antiproliferative and DNA binding activities.
Bilanges B, Varrault A, Mazumdar A, Pantaloni C, Hoffmann A, Bockaert J, Spengler D, Journot L
Oncogene. 2001 ; 20 (10) : 1246-1253.
PMID 11313869
 
Enhancement of p53-dependent gene activation by the transcriptional coactivator Zac1.
Huang SM, Schˆnthal AH, Stallcup MR
Oncogene. 2001 ; 20 (17) : 2134-2143.
PMID 11360197
 
Expression pattern of Zac1 mouse gene, a new zinc-finger protein that regulates apoptosis and cellular cycle arrest, in both adult brain and along development.
Valente T, Auladell C
Mechanisms of development. 2001 ; 108 (1-2) : 207-211.
PMID 11578877
 
Characterization of the methylation-sensitive promoter of the imprinted ZAC gene supports its role in transient neonatal diabetes mellitus.
Varrault A, Bilanges B, Mackay DJ, Basyuk E, Ahr B, Fernandez C, Robinson DO, Bockaert J, Journot L
The Journal of biological chemistry. 2001 ; 276 (22) : 18653-18656.
PMID 11297535
 
The tumorigenic diversity of the three PLAG family members is associated with different DNA binding capacities.
Hensen K, Van Valckenborgh IC, Kas K, Van de Ven WJ, Voz ML
Cancer research. 2002 ; 62 (5) : 1510-1517.
PMID 11888928
 
Relaxation of imprinted expression of ZAC and HYMAI in a patient with transient neonatal diabetes mellitus.
Mackay DJ, Coupe AM, Shield JP, Storr JN, Temple IK, Robinson DO
Human genetics. 2002 ; 110 (2) : 139-144.
PMID 11935319
 
The mouse Zac1 locus: basis for imprinting and comparison with human ZAC.
Smith RJ, Arnaud P, Konfortova G, Dean WL, Beechey CV, Kelsey G
Gene. 2002 ; 292 (1-2) : 101-112.
PMID 12119104
 
LOT1 (PLAGL1/ZAC1), the candidate tumor suppressor gene at chromosome 6q24-25, is epigenetically regulated in cancer.
Abdollahi A, Pisarcik D, Roberts D, Weinstein J, Cairns P, Hamilton TC
The Journal of biological chemistry. 2003 ; 278 (8) : 6041-6049.
PMID 12473647
 
Developmental expression of the cell cycle and apoptosis controlling gene, Lot1, in the rat cerebellum and in cultures of cerebellar granule cells.
Ciani E, Frenquelli M, Contestabile A
Brain research. Developmental brain research. 2003 ; 142 (2) : 193-202.
PMID 12711370
 
Transcriptional activities of the zinc finger protein Zac are differentially controlled by DNA binding.
Hoffmann A, Ciani E, Boeckardt J, Holsboer F, Journot L, Spengler D
Molecular and cellular biology. 2003 ; 23 (3) : 988-1003.
PMID 12529403
 
Altered expression and loss of heterozygosity of the LOT1 gene in ovarian cancer.
Cvetkovic D, Pisarcik D, Lee C, Hamilton TC, Abdollahi A
Gynecologic oncology. 2004 ; 95 (3) : 449-455.
PMID 15581945
 
Loss of expression of ZAC/LOT1 in squamous cell carcinomas of head and neck.
Koy S, Hauses M, Appelt H, Friedrich K, Schackert HK, Eckelt U
Head & neck. 2004 ; 26 (4) : 338-344.
PMID 15054737
 
Zac1 is up-regulated in neural cells of the limbic system of mouse brain following seizures that provoke strong cell activation.
Valente T, Domˆ‚nguez MI, Bellmann A, Journot L, Ferrer I, Auladell C
Neuroscience. 2004 ; 128 (2) : 323-336.
PMID 15350644
 
ZAC, LIT1 (KCNQ1OT1) and p57KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome.
Arima T, Kamikihara T, Hayashida T, Kato K, Inoue T, Shirayoshi Y, Oshimura M, Soejima H, Mukai T, Wake N
Nucleic acids research. 2005 ; 33 (8) : 2650-2660.
PMID 15888726
 
The candidate tumor suppressor gene ZAC is involved in keratinocyte differentiation and its expression is lost in basal cell carcinomas.
Basyuk E, Coulon V, Le Digarcher A, Coisy-Quivy M, Moles JP, Gandarillas A, Journot L
Molecular cancer research : MCR. 2005 ; 3 (9) : 483-492.
PMID 16179495
 
Cyclic AMP-mediated regulation of transcription factor Lot1 expression in cerebellar granule cells.
Contestabile A, Fila T, Bartesaghi R, Ciani E
The Journal of biological chemistry. 2005 ; 280 (39) : 33541-33551.
PMID 16061485
 
Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer.
Kamikihara T, Arima T, Kato K, Matsuda T, Kato H, Douchi T, Nagata Y, Nakao M, Wake N
International journal of cancer. Journal international du cancer. 2005 ; 115 (5) : 690-700.
PMID 15751035
 
The PLAGL1 gene is down-regulated in human extraskeletal myxoid chondrosarcoma tumors.
Poulin H, Labelle Y
Cancer letters. 2005 ; 227 (2) : 185-191.
PMID 16112421
 
Zac1 is expressed in progenitor/stem cells of the neuroectoderm and mesoderm during embryogenesis: differential phenotype of the Zac1-expressing cells during development.
Valente T, Junyent F, Auladell C
Developmental dynamics : an official publication of the American Association of Anatomists. 2005 ; 233 (2) : 667-679.
PMID 15844099
 
The human HYMAI/PLAGL1 differentially methylated region acts as an imprint control region in mice.
Arima T, Yamasaki K, John RM, Kato K, Sakumi K, Nakabeppu Y, Wake N, Kono T
Genomics. 2006 ; 88 (5) : 650-658.
PMID 16928428
 
Establishment of the primary imprint of the HYMAI/PLAGL1 imprint control region during oogenesis.
Arima T, Wake N
Cytogenetic and genome research. 2006 ; 113 (1-4) : 247-252.
PMID 16575187
 
Peroxisome proliferator-activated receptor gamma is a Zac target gene mediating Zac antiproliferation.
Barz T, Hoffmann A, Panhuysen M, Spengler D
Cancer research. 2006 ; 66 (24) : 11975-11982.
PMID 17178896
 
Multitasking C2H2 zinc fingers link Zac DNA binding to coordinated regulation of p300-histone acetyltransferase activity.
Hoffmann A, Barz T, Spengler D
Molecular and cellular biology. 2006 ; 26 (14) : 5544-5557.
PMID 16809786
 
Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth.
Varrault A, Gueydan C, Delalbre A, Bellmann A, Houssami S, Aknin C, Severac D, Chotard L, Kahli M, Le Digarcher A, Pavlidis P, Journot L
Developmental cell. 2006 ; 11 (5) : 711-722.
PMID 17084362
 
LOT1 (ZAC1/PLAGL1) and its family members: mechanisms and functions.
Abdollahi A
Journal of cellular physiology. 2007 ; 210 (1) : 16-25.
PMID 17063461
 
DFsn collaborates with Highwire to down-regulate the Wallenda/DLK kinase and restrain synaptic terminal growth.
Wu C, Daniels RW, Diantonio A
Neural development. 2007 ; 2 : page 16.
PMID 17697379
 
Tissue-specific imprinting of the ZAC/PLAGL1 tumour suppressor gene results from variable utilization of monoallelic and biallelic promoters.
Valleley EM, Cordery SF, Bonthron DT
Human molecular genetics. 2007 ; 16 (8) : 972-981.
PMID 17341487
 
Physical and functional interactions of human papillomavirus E2 protein with nuclear receptor coactivators.
Wu MH, Huang CJ, Liu ST, Liu PY, Ho CL, Huang SM
Biochemical and biophysical research communications. 2007 ; 356 (3) : 523-528.
PMID 17376404
 
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Contributor(s)

Written08-2007Abbas Abdollahi
Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, BioLife Sciences Building, Suite 446, Temple University, 1900 North 12th Street, Philadelphia, PA 19122, USA

Citation

This paper should be referenced as such :
Abdollahi, A
PLAGL1 (pleomorphic adenoma gene-like 1)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2):127-129.
Free journal version : [ pdf ]   [ DOI ]
URL : http://AtlasGeneticsOncology.org/Genes/PLAGL1ID41737ch6q24.html

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