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AMER1 (APC membrane recruitment protein 1)

Written2009-01E Cristy Ruteshouser
University of Texas M D Anderson Cancer Center, Department of Genetics, 1515 Holcombe Blvd, Houston TX 77030, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesFAM123B
family with sequence similarity 123B
Alias_symbol (synonym)RP11-403E24.2
FLJ39827
WTX
Other aliasFAM123B (family with sequence similarity 123B)
WTX (Wilms Tumor on the X chromosome)
AMER1 (APC MEmbrane Recruitment 1)
OTTHUMP00000196469
HGNC (Hugo) AMER1
LocusID (NCBI) 139285
Atlas_Id 44119
Location Xq11.2  [Link to chromosome band Xq11]
Location_base_pair Starts at 64185117 and ends at 64205744 bp from pter ( according to hg19-Feb_2009)  [Mapping AMER1.png]
Local_order Cen-ARHGEF9-WTX-ASB12-Ter

DNA/RNA

Description 2 or 3 exons spanning 18-21kb genomic DNA.
Transcription FAM123B is predicted to generate an mRNA of 8.4kb. The WTX/FAM123B gene is transcribed as a 7.5kb mRNA; an alternatively spliced transcript 831nt shorter has been observed in human primary cell lines, generated by use of a splice donor and splice acceptor site both located within exon 2. Exon 1 is noncoding. The entire ORF of the 7.5kb mRNA is contained within a single exon.
Pseudogene No known pseudogenes.

Protein

 
  The 1135 amino acid WTX protein. Black box, the two phosphatidylinositol(4,5)-bisphosphate-binding domains (PtdIns(4,5)P2). Open boxes, the three APC binding domains (APCBD1, APCBD2, APCBD3). Acidic, the acidic domain. NLS, the predicted nuclear localization signal. CC, coiled-coil domain. PR, proline-rich region. Horizontal lines indicate the 277aa not present in the 858aa WTX isoform 2 and the beta-catenin binding region.
Description Two isoforms (858-1135aa) due to alternative splicing. The 858aa WTX isoform 2 lacks amino acids 50-326 of the larger isoform.
Expression Ubiquitous.
Localisation Plasma membrane (1135aa isoform), nucleus (858aa isoform).
Function The N-terminus of the WTX protein has a predicted nuclear localization signal (NLS; residues 166-182), and 2 phosphatidylinositol(4,5)-bisphosphate-binding domains (PtdIns(4,5)P2; residues 2-142 and 143-209) that are involved in its localization to the plasma membrane. The WTX protein also has 3 adenomatous polyposis coli (APC) binding domains (APCBD1, residues 280-368; APCBD2, 380-531; and APCBD3, 717-834) that mediate its interaction with the armadillo (ARM) repeats of the tumor suppressor APC, as well as a beta-catenin binding site (located between residue 367 and the C-terminus), an acidic domain (residues 370-411), two coiled-coil domains (residues 374-403 and 574-593) and a proline-rich region (residues 951-1104).
The 858aa isoform is missing both PtdIns(4,5)P2 binding domains and localizes to the nucleus in a punctate pattern. Interestingly, this shorter isoform lacks the predicted NLS, and the longer isoform that includes the predicted NLS localizes to the plasma membrane.
WTX forms a protein complex with beta-catenin, AXIN1, beta-transducin repeat-containing protein 2 (beta-TrCP2) and APC and negatively regulates the WNT signaling pathway by promoting the ubiquitination and degradation of beta-catenin. WTX also plays a role in the recruitment of APC from microtubules to the plasma membrane and appears to be involved in the maintenance of intercellular junctions.
Homology The amino terminus of WTX shows homology to FAM123A; 32% identical over 586aa. The regions with the highest percentage identity include the predicted NLS, the APCBD1 and APCBD2 binding domains, and the acidic domain.

Mutations

Note Mutational analysis of the WTX gene in gastric, colorectal, and hepatocellular carcinomas and in acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) showed no deletion or truncating mutations of WTX. Missense mutations were found in 1/47 colorectal carcinomas and 1/60 normal karyotype AML cases. Various missense mutations (D233Y, K292N, E395D, R584G, Y599C, P880L, P884L, and I1003M) found in Wilms tumors were also in most cases found in normal tissues from the same patient. The missense mutations seen in the one colorectal carcinoma and one AML were tumor-specific. Although these are not currently known to be SNPs (dbSNP, build 129), they may not constitute functional mutations in WTX.
Inactivating mutations in WTX (deletions and truncating/frameshift mutations) appear to be negatively correlated in Wilms tumors with activating mutations in exon 3 of CTNNB1 (encoding beta-catenin), implicating the activation of the WNT signaling pathway in the formation of Wilms tumors since both inactivating mutations of WTX and activating mutations of CTNNB1 function to activate this signaling pathway.
Germinal In osteopathia striata congenita with cranial stenosis (OSCS), deletions of the entire WTX gene and truncation mutations (nonsense mutations and deletion/insertion + frameshift mutations) have been observed. In cases with truncation mutations in which the mutations affect nucleotides 285-1112 (encoding residues 50-326), the mutations reside within intron 2 of the shorter alternatively spliced transcript and do not affect the 858aa isoform. However, such mutations are lethal in males and demonstrate a typical clinical phenotype in females, suggesting that retention of the wild-type 858aa isoform of WTX cannot compensate in terms of regulation of the WNT signaling pathway for loss or truncation of the 1135aa isoform.
Somatic In Wilms tumors, the most commonly observed mutation is the deletion of the entire WTX gene. Truncation mutations and missense mutations have also been observed.

Implicated in

Note
  
Entity Wilms tumor (nephroblastoma)
Prognosis The overall five-year survival is approximately 90%. Prognosis for Wilms tumor is excellent for favorable histology tumors with treatment according to Children's Oncology Group (COG) or Société Internationale d'Oncologie Pédiatrique (SIOP) protocols. The prognosis is less good for Wilms tumors with anaplastic histology, particularly those with diffuse anaplasia for which the overall four-year survival is approximately 65%.
Cytogenetics Balanced translocation t(X;18)(q11;p11) with WTX deletion; Xq11.1 deletions.
Oncogenesis 7-29% of Wilms tumors show deletions or mutations of WTX.
  
  
Entity Osteopathia striata congenita with cranial sclerosis (OSCS) (MIM300373)
Note The severity of the OSCS phenotype appears to be correlated, in cases with truncating mutations in WTX, with the location of the truncating mutation, with truncations C-terminal to the acidic domain (residues 370-411) associated with a less severe phenotype, at least in males.
Prognosis Most males with OSCS die at or before birth. Females with OSCS show multiple defects including sclerosis of the long bones and skull, longitudinal striations of osteosclerosis in the long bones, macrocephaly, and cleft palate.
Cytogenetics X-linked dominant inheritance.
Oncogenesis OSCS individuals with germline mutations in WTX do not appear to be predisposed to Wilms tumor or other malignancies.
  

Bibliography

Tumor suppressor WTX gene mutation is rare in acute leukemias.
Chung NG, Kim MS, Chung YJ, Yoo NJ, Lee SH.
Leuk Lymphoma. 2008 Aug;49(8):1616-7.
PMID 18452086
 
Canonical WNT signalling determines lineage specificity in Wilms tumour.
Fukuzawa R, Anaka MR, Weeks RJ, Morison IM, Reeve AE.
Oncogene. 2009 Jan 12. [Epub ahead of print]
PMID 19137020
 
AMER1 regulates the distribution of the tumor suppressor APC between microtubules and the plasma membrane.
Grohmann A, Tanneberger K, Alzner A, Schneikert J, Behrens J.
J Cell Sci. 2007 Nov 1;120(Pt 21):3738-47. Epub 2007 Oct 9.
PMID 17925383
 
Wilms' tumor with an apparently balanced translocation t(X;18) resulting in deletion of the WTX gene.
Han M, Rivera MN, Batten JM, Haber DA, Dal Cin P, Iafrate AJ.
Genes Chromosomes Cancer. 2007 Oct;46(10):909-13.
PMID 17620295
 
Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis.
Jenkins ZA, van Kogelenberg M, Morgan T, Jeffs A, Fukuzawa R, Pearl E, Thaller C, Hing AV, Porteous ME, Garcia-Minaur S, Bohring A, Lacombe D, Stewart F, Fiskerstrand T, Bindoff L, Berland S, Ades LC, Tchan M, David A, Wilson LC, Hennekam RC, Donnai D, Mansour S, Cormier-Daire V, Robertson SP.
Nat Genet. 2009 Jan;41(1):95-100. Epub 2008 Dec 14.
PMID 19079258
 
Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling.
Major MB, Camp ND, Berndt JD, Yi X, Goldenberg SJ, Hubbert C, Biechele TL, Gingras AC, Zheng N, Maccoss MJ, Angers S, Moon RT.
Science. 2007 May 18;316(5827):1043-6.
PMID 17510365
 
WTX is rarely mutated in acute myeloid leukemia.
Owen C, Virappane P, Alikian M, Stasevich I, Summers K, Lillington D, Bonnet D, Burnett A, Mills K, Lister TA, Fitzgibbon J.
Haematologica. 2008 Jun;93(6):947-8. Epub 2008 May 6.
PMID 18460646
 
Functional inactivation of the WTX gene is not a frequent event in Wilms' tumors.
Perotti D, Gamba B, Sardella M, Spreafico F, Terenziani M, Collini P, Pession A, Nantron M, Fossati-Bellani F, Radice P.
Oncogene. 2008 Jul 31;27(33):4625-32. Epub 2008 Apr 7.
PMID 18391980
 
An X chromosome gene, WTX, is commonly inactivated in Wilms tumor.
Rivera MN, Kim WJ, Wells J, Driscoll DR, Brannigan BW, Han M, Kim JC, Feinberg AP, Gerald WL, Vargas SO, Chin L, Iafrate AJ, Bell DW, Haber DA.
Science. 2007 Feb 2;315(5812):642-5. Epub 2007 Jan 4.
PMID 17204608
 
Wilms tumor genetics: mutations in WT1, WTX, and CTNNB1 account for only about one-third of tumors.
Ruteshouser EC, Robinson SM, Huff V.
Genes Chromosomes Cancer. 2008 Jun;47(6):461-70.
PMID 18311776
 
Mutational Analysis of WTX Gene in Wnt/ beta-Catenin Pathway in Gastric, Colorectal, and Hepatocellular Carcinomas.
Yoo NJ, Kim S, Lee SH.
Dig Dis Sci. 2008 Aug 22. [Epub ahead of print]
PMID 18720004
 

Citation

This paper should be referenced as such :
Ruteshouser, EC
FAM123B (family with sequence similarity 123B)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(12):932-934.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/FAM123BID44119chXq11.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Colon: Colorectal adenocarcinoma


External links

Nomenclature
HGNC (Hugo)AMER1   26837
Cards
AtlasFAM123BID44119chXq11
Entrez_Gene (NCBI)AMER1  139285  APC membrane recruitment protein 1
AliasesFAM123B; OSCS; WTX
GeneCards (Weizmann)AMER1
Ensembl hg19 (Hinxton)ENSG00000184675 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000184675 [Gene_View]  chrX:64185117-64205744 [Contig_View]  AMER1 [Vega]
ICGC DataPortalENSG00000184675
TCGA cBioPortalAMER1
AceView (NCBI)AMER1
Genatlas (Paris)AMER1
WikiGenes139285
SOURCE (Princeton)AMER1
Genetics Home Reference (NIH)AMER1
Genomic and cartography
GoldenPath hg38 (UCSC)AMER1  -     chrX:64185117-64205744 -  Xq11.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)AMER1  -     Xq11.2   [Description]    (hg19-Feb_2009)
EnsemblAMER1 - Xq11.2 [CytoView hg19]  AMER1 - Xq11.2 [CytoView hg38]
Mapping of homologs : NCBIAMER1 [Mapview hg19]  AMER1 [Mapview hg38]
OMIM300373   300647   
Gene and transcription
Genbank (Entrez)AK097146 AL833759 DA939151 EF186024
RefSeq transcript (Entrez)NM_152424
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)AMER1
Cluster EST : UnigeneHs.314225 [ NCBI ]
CGAP (NCI)Hs.314225
Alternative Splicing GalleryENSG00000184675
Gene ExpressionAMER1 [ NCBI-GEO ]   AMER1 [ EBI - ARRAY_EXPRESS ]   AMER1 [ SEEK ]   AMER1 [ MEM ]
Gene Expression Viewer (FireBrowse)AMER1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)139285
GTEX Portal (Tissue expression)AMER1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ5JTC6   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ5JTC6  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ5JTC6
Splice isoforms : SwissVarQ5JTC6
PhosPhoSitePlusQ5JTC6
Domains : Interpro (EBI)Uncharacterised_FAM123   
Domain families : Pfam (Sanger)WTX (PF09422)   
Domain families : Pfam (NCBI)pfam09422   
Conserved Domain (NCBI)AMER1
DMDM Disease mutations139285
Blocks (Seattle)AMER1
PDB (SRS)4YJE    4YJL    4YK6   
PDB (PDBSum)4YJE    4YJL    4YK6   
PDB (IMB)4YJE    4YJL    4YK6   
PDB (RSDB)4YJE    4YJL    4YK6   
Structural Biology KnowledgeBase4YJE    4YJL    4YK6   
SCOP (Structural Classification of Proteins)4YJE    4YJL    4YK6   
CATH (Classification of proteins structures)4YJE    4YJL    4YK6   
SuperfamilyQ5JTC6
Human Protein AtlasENSG00000184675
Peptide AtlasQ5JTC6
HPRD06565
IPIIPI00167391   IPI00844450   
Protein Interaction databases
DIP (DOE-UCLA)Q5JTC6
IntAct (EBI)Q5JTC6
FunCoupENSG00000184675
BioGRIDAMER1
STRING (EMBL)AMER1
ZODIACAMER1
Ontologies - Pathways
QuickGOQ5JTC6
Ontology : AmiGOprotein binding  phosphatidylinositol-4,5-bisphosphate binding  phosphatidylinositol-4,5-bisphosphate binding  cytosol  plasma membrane  beta-catenin binding  beta-catenin binding  Wnt signaling pathway  nuclear body  positive regulation of protein ubiquitination  proteasome-mediated ubiquitin-dependent protein catabolic process  intracellular membrane-bounded organelle  anatomical structure development  bone development  adipose tissue development  regulation of canonical Wnt signaling pathway  mesenchymal cell differentiation involved in kidney development  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  positive regulation of canonical Wnt signaling pathway  positive regulation of cellular protein catabolic process  beta-catenin destruction complex binding  beta-catenin destruction complex assembly  beta-catenin destruction complex disassembly  
Ontology : EGO-EBIprotein binding  phosphatidylinositol-4,5-bisphosphate binding  phosphatidylinositol-4,5-bisphosphate binding  cytosol  plasma membrane  beta-catenin binding  beta-catenin binding  Wnt signaling pathway  nuclear body  positive regulation of protein ubiquitination  proteasome-mediated ubiquitin-dependent protein catabolic process  intracellular membrane-bounded organelle  anatomical structure development  bone development  adipose tissue development  regulation of canonical Wnt signaling pathway  mesenchymal cell differentiation involved in kidney development  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  positive regulation of canonical Wnt signaling pathway  positive regulation of cellular protein catabolic process  beta-catenin destruction complex binding  beta-catenin destruction complex assembly  beta-catenin destruction complex disassembly  
REACTOMEQ5JTC6 [protein]
REACTOME PathwaysR-HSA-5467348 [pathway]   
NDEx NetworkAMER1
Atlas of Cancer Signalling NetworkAMER1
Wikipedia pathwaysAMER1
Orthology - Evolution
OrthoDB139285
GeneTree (enSembl)ENSG00000184675
Phylogenetic Trees/Animal Genes : TreeFamAMER1
HOVERGENQ5JTC6
HOGENOMQ5JTC6
Homologs : HomoloGeneAMER1
Homology/Alignments : Family Browser (UCSC)AMER1
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerAMER1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)AMER1
dbVarAMER1
ClinVarAMER1
1000_GenomesAMER1 
Exome Variant ServerAMER1
ExAC (Exome Aggregation Consortium)AMER1 (select the gene name)
Genetic variants : HAPMAP139285
Genomic Variants (DGV)AMER1 [DGVbeta]
DECIPHERAMER1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisAMER1 
Mutations
ICGC Data PortalAMER1 
TCGA Data PortalAMER1 
Broad Tumor PortalAMER1
OASIS PortalAMER1 [ Somatic mutations - Copy number]
Cancer Gene: CensusAMER1 
Somatic Mutations in Cancer : COSMICAMER1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDAMER1
intOGen PortalFAM123B
BioMutasearch AMER1
DgiDB (Drug Gene Interaction Database)AMER1
DoCM (Curated mutations)AMER1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)AMER1 (select a term)
intoGenAMER1
NCG5 (London)AMER1
Cancer3DAMER1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM300373    300647   
Orphanet2529   
MedgenAMER1
Genetic Testing Registry AMER1
NextProtQ5JTC6 [Medical]
TSGene139285
GENETestsAMER1
Target ValidationAMER1
Huge Navigator AMER1 [HugePedia]
snp3D : Map Gene to Disease139285
BioCentury BCIQAMER1
ClinGenAMER1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD139285
Chemical/Pharm GKB GenePA145148904
Drug Sensitivity AMER1
Clinical trialAMER1
Miscellaneous
canSAR (ICR)AMER1 (select the gene name)
Probes
Litterature
PubMed52 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineAMER1
EVEXAMER1
GoPubMedAMER1
iHOPAMER1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Jun 7 12:02:26 CEST 2017

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