AMER1 (APC membrane recruitment protein 1)

2009-01-01   E Cristy Ruteshouser 

University of Texas M D Anderson Cancer Center, Department of Genetics, 1515 Holcombe Blvd, Houston TX 77030, USA


FAM123B (family with sequence similarity 123B),WTX (Wilms Tumor on the X chromosome),AMER1 (APC MEmbrane Recruitment 1),FLJ39827,OTTHUMP00000196469,RP11-403E24.2



2 or 3 exons spanning 18-21kb genomic DNA.


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.


No known pseudogenes.


Atlas Image
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.


Two isoforms (858-1135aa) due to alternative splicing. The 858aa WTX isoform 2 lacks amino acids 50-326 of the larger isoform.




Plasma membrane (1135aa isoform), nucleus (858aa isoform).


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.


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.



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.


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.


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

Entity name
Wilms tumor (nephroblastoma)
The overall five-year survival is approximately 90%. Prognosis for Wilms tumor is excellent for favorable histology tumors with treatment according to Childrens Oncology Group (COG) or Société Internationale dOncologie 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%.
Balanced translocation t(X;18)(q11;p11) with WTX deletion; Xq11.1 deletions.
7-29% of Wilms tumors show deletions or mutations of WTX.
Entity name
Osteopathia striata congenita with cranial sclerosis (OSCS) (MIM300373)
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.
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.
X-linked dominant inheritance.
OSCS individuals with germline mutations in WTX do not appear to be predisposed to Wilms tumor or other malignancies.


Pubmed IDLast YearTitleAuthors
184520862008Tumor suppressor WTX gene mutation is rare in acute leukemias.Chung NG et al
191370202009Canonical WNT signalling determines lineage specificity in Wilms tumour.Fukuzawa R et al
179253832007AMER1 regulates the distribution of the tumor suppressor APC between microtubules and the plasma membrane.Grohmann A et al
176202952007Wilms' tumor with an apparently balanced translocation t(X;18) resulting in deletion of the WTX gene.Han M et al
190792582009Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis.Jenkins ZA et al
175103652007Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling.Major MB et al
184606462008WTX is rarely mutated in acute myeloid leukemia.Owen C et al
183919802008Functional inactivation of the WTX gene is not a frequent event in Wilms' tumors.Perotti D et al
172046082007An X chromosome gene, WTX, is commonly inactivated in Wilms tumor.Rivera MN et al
183117762008Wilms tumor genetics: mutations in WT1, WTX, and CTNNB1 account for only about one-third of tumors.Ruteshouser EC et al
187200042009Mutational analysis of WTX gene in Wnt/ beta-catenin pathway in gastric, colorectal, and hepatocellular carcinomas.Yoo NJ et al

Other Information

Locus ID:

NCBI: 139285
MIM: 300647
HGNC: 26837
Ensembl: ENSG00000184675


dbSNP: 139285
ClinVar: 139285
TCGA: ENSG00000184675


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by WNT in cancerREACTOMER-HSA-4791275
truncated APC mutants destabilize the destruction complexREACTOMER-HSA-4839744
APC truncation mutants have impaired AXIN bindingREACTOMER-HSA-5467337
AXIN mutants destabilize the destruction complex, activating WNT signalingREACTOMER-HSA-4839735
AXIN missense mutants destabilize the destruction complexREACTOMER-HSA-5467340
AMER1 mutants destabilize the destruction complexREACTOMER-HSA-4839748
Truncations of AMER1 destabilize the destruction complexREACTOMER-HSA-5467348
phosphorylation site mutants of CTNNB1 are not targeted to the proteasome by the destruction complexREACTOMER-HSA-4839743
S45 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358751
T41 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358752
S37 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358749
S33 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358747
Misspliced GSK3beta mutants stabilize beta-cateninREACTOMER-HSA-5339716
Signal TransductionREACTOMER-HSA-162582
Signaling by WntREACTOMER-HSA-195721
Degradation of beta-catenin by the destruction complexREACTOMER-HSA-195253
Beta-catenin phosphorylation cascadeREACTOMER-HSA-196299
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Disassembly of the destruction complex and recruitment of AXIN to the membraneREACTOMER-HSA-4641262

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
175103652007Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling.155
172046082007An X chromosome gene, WTX, is commonly inactivated in Wilms tumor.103
183117762008Wilms tumor genetics: mutations in WT1, WTX, and CTNNB1 account for only about one-third of tumors.55
190792582009Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis.39
222156752012Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein.37
193518172009Genetic mutations associated with cigarette smoking in pancreatic cancer.34
179253832007AMER1 regulates the distribution of the tumor suppressor APC between microtubules and the plasma membrane.32
260714832015Exome Sequencing Reveals AMER1 as a Frequently Mutated Gene in Colorectal Cancer.23
194168062009The tumor suppressor WTX shuttles to the nucleus and modulates WT1 activity.22
222857522012The WTX tumor suppressor enhances p53 acetylation by CBP/p300.22


E Cristy Ruteshouser

AMER1 (APC membrane recruitment protein 1)

Atlas Genet Cytogenet Oncol Haematol. 2009-01-01

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