AMER1

Summary

AMER1 (APC membrane recruitment protein 1, HGNC:26837) is a protein-coding gene on chromosome Xq11.2, encoding APC membrane recruitment protein 1 (Q5JTC6). Regulator of the canonical Wnt signaling pathway.

The protein encoded by this gene upregulates trancriptional activation by the Wilms tumor protein and interacts with many other proteins, including CTNNB1, APC, AXIN1, and AXIN2. Defects in this gene are a cause of osteopathia striata with cranial sclerosis (OSCS).

Source: NCBI Gene 139285 — RefSeq curated summary.

At a glance

• Gene–disease (curated): osteopathia striata with cranial sclerosis (Definitive, ClinGen)
• Clinical variants (ClinVar): 672 total — 37 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 100
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 4 cancer types
• MANE Select transcript: NM_152424

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26837
Approved symbol	AMER1
Name	APC membrane recruitment protein 1
Location	Xq11.2
Locus type	gene with protein product
Status	Approved
Aliases	RP11-403E24.2, FLJ39827, WTX
Ensembl gene	ENSG00000184675
Ensembl biotype	protein_coding
OMIM	300647
Entrez	139285

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000374869

RefSeq mRNA: 1 — MANE Select: NM_152424 NM_152424

CCDS: CCDS14377

Canonical transcript exons

ENST00000374869 — 2 exons

Exon	Start	End
ENSE00001298168	64185117	64193384
ENSE00003838683	64205570	64205708

Expression profiles

Bgee: expression breadth ubiquitous, 156 present calls, max score 78.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2.6034 / max 40.2507, expressed in 1068 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199475	2.6034	1068

Top tissues by expression

244 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	78.50	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	76.98	gold quality
myocardium	UBERON:0002349	76.00	gold quality
hindlimb stylopod muscle	UBERON:0004252	75.42	gold quality
muscle of leg	UBERON:0001383	73.64	gold quality
gastrocnemius	UBERON:0001388	73.59	gold quality
ganglionic eminence	UBERON:0004023	72.70	gold quality
smooth muscle tissue	UBERON:0001135	71.11	gold quality
ventricular zone	UBERON:0003053	70.78	gold quality
left ovary	UBERON:0002119	70.17	gold quality
superficial temporal artery	UBERON:0001614	70.09	gold quality
right ovary	UBERON:0002118	69.60	gold quality
ovary	UBERON:0000992	69.47	gold quality
muscle tissue	UBERON:0002385	68.54	gold quality
skeletal muscle tissue	UBERON:0001134	68.48	gold quality
oviduct epithelium	UBERON:0004804	68.35	gold quality
stromal cell of endometrium	CL:0002255	68.29	gold quality
right lobe of liver	UBERON:0001114	68.24	gold quality
sural nerve	UBERON:0015488	68.06	gold quality
adrenal tissue	UBERON:0018303	67.95	gold quality
colonic epithelium	UBERON:0000397	67.83	silver quality
popliteal artery	UBERON:0002250	67.69	gold quality
lower esophagus mucosa	UBERON:0035834	67.69	gold quality
tibial artery	UBERON:0007610	67.67	gold quality
sperm	CL:0000019	67.43	gold quality
esophagus mucosa	UBERON:0002469	67.29	gold quality
leukocyte	CL:0000738	67.17	gold quality
monocyte	CL:0000576	66.96	gold quality
aorta	UBERON:0000947	66.86	gold quality
esophagus	UBERON:0001043	66.81	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.63

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): WT1, ZNF354C

miRNA regulators (miRDB)

229 targeting AMER1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6778-3P	99.96	67.29	2693

Literature-anchored findings (GeneRIF, showing 39)

• WTX, is inactivated in approximately one-third of Wilms tumors; it is inactivated by a monoallelic “single-hit” event targeting the single X chromosome in tumors from males and the active X chromosome in tumors from females (PMID:17204608)
• findings show that WTX, a protein encoded by a gene mutated in Wilms tumors, forms a complex with beta-catenin, AXIN1, beta-TrCP2 and APC; data provide a possible mechanistic explanation for the tumor suppressor activity of WTX (PMID:17510365)
• Deletion of the WTX gene is associated with Wilms’ tumor with a balanced translocation t(X;18) (PMID:17620295)
• These data indicate that AMER1 controls the subcellular distribution of APC between membrane- and microtubule-associated pools, and might thereby regulate APC-dependent cellular morphogenesis, cell migration and cell-cell adhesion. (PMID:17925383)
• Gene has a tumor suppressor function in Wilms tumors, and is involved in beta-catenin destruction. (PMID:18021721)
• WT1 and WTX mutations occur with similar frequency, that they partially overlap in Wilms tumors, and that mutations in WT1, WTX, and CTNNB1 underlie the genetic basis of about one-third of Wilms tumors (PMID:18311776)
• Functional inactivation of the WTX gene is not a frequent event in Wilms’ tumors. (PMID:18391980)
• there was not any evidence of WTX mutation in the 143 acute leukemia patients (PMID:18452086)
• WTX is rarely mutated in acute myeloid leukemia (PMID:18460646)
• Data indicate that WTX mutation is rare in colorectal, gastric, and hepatocellular carcinomas. (PMID:18720004)
• The observed phenotypic discordance dependent upon whether a mutation is germline or occurs somatically suggests the existence of temporal or spatial constraints on the action of WTX during tumorigenesis. (PMID:19079258)
• Mutations in WTX gene is associated with Wilms tumor. (PMID:19137020)
• WTX binds WT1 and enhances WT1-mediated transcription, suggesting a role for WTX in nuclear pathways implicated in the transcriptional regulation of cellular differentiation programs (PMID:19416806)
• inactivation of WTX appears to be a late event in tumorigenesis of nephroblastoma in a subgroup of nephroblastomas (PMID:19757195)
• WTX inactivation is associated with Wilms tumors (PMID:19760609)
• All investigated families diagnosed with Osteopathia striata with cranial sclerosis had WTX gene defects. (PMID:20209645)
• WTX mutations can arise both early and late in Wilms tumour development (PMID:20679664)
• Mutations in the WTX-gene are associated with high-grade microsatellite instable colorectal cancers. (PMID:20696052)
• Two novel WTX mutations underscore the unpredictability of male survival in osteopathia striata with cranial sclerosis. (PMID:20950377)
• When gene expression changes mediated by wild-type WTX were compared with those affected by mutant WTX, WTX565 had a 55% overlap in differentially regulated genes, whereas WTX358 regulated only two genes affected by wild-type WTX. (PMID:20956941)
• Amer1 exerts its negative regulatory role in Wnt signaling by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the plasma membrane. (PMID:21498506)
• WTX and NRF2 compete for binding to KEAP1, and thus loss of WTX leads to rapid ubiquitination and degradation of NRF2 and a reduced response to cytotoxic insult. (PMID:22215675)
• WTX modulates p53 function, in part through regulation of its activator CBP/p300. (PMID:22285752)
• Data indicate that osteopathia striata congenita with cranial sclerosis (OSCS) iscaused by germline deletions of in the X-linked gene WTX (FAM123B, AMER1). (PMID:22670894)
• Osteopathia striata with cranial sclerosis or Horan-Beighton syndrome is a rare X-linked dominant inherited bone dysplasia. Genetic analysis allowed the identification of maternally transmitted heterozygous nonsense c.1057C>T (p.R353X) WTX mutation. (PMID:22716240)
• WTX mutations occur early in Wilms’ tumor development, but at a low proportion. There was no evidence that WTX is the main cause of Wilms’ tumor. (PMID:22800892)
• Stat3 inhibits WTX expression through up-regulation of micro RNA-370 in Wilms tumor. (PMID:23333300)
• WTX inactivation occurs in a wider variety of tumor types than previously appreciated and point to shared pathogenic mechanisms between a subset of pediatric malignancies. (PMID:24249259)
• Data show that beta-arrestins regulate Wnt3a-induced low density lipoprotein receptor-related protein 6 (Lrp6) phosphorylation by the regulation of the membrane dynamics of Amer1. (PMID:24265322)
• A nonsense mutation (c.1045C>T, p.Glu349*) in the WTX gene. (PMID:24459086)
• Losses of AMER1 by other mechanisms apart from mutations. (PMID:26071483)
• This study revealed no clinical or pathologic distinctions between Wilms tumor (WT) with and without WTX mutation. This similarity lends support to the concept of a common tumorigenic pathway between WT with aberrant WTX and those without. (PMID:28326956)
• A novel heterozygous frameshift mutation in AMER1 was identified in a patient with osteopathia striata with cranial sclerosis. (PMID:28893644)
• found that miR-4524b-5p could regulate the migration and invasion of cervical cancer by targeting WTX and that WTX could regulate the expression of beta-catenin (PMID:30939162)
• KIF23 activated Wnt/beta-catenin signaling pathway through direct interaction with Amer1 in gastric cancer. (PMID:32365332)
• Deletion of Exon 1 in AMER1 in Osteopathia Striata with Cranial Sclerosis. (PMID:33265914)
• The phenotypic spectrum of AMER1-related osteopathia striata with cranial sclerosis: The first Canadian cohort. (PMID:34414661)
• IRF-2 inhibits cancer proliferation by promoting AMER-1 transcription in human gastric cancer. (PMID:35115027)
• AMER1 deficiency promotes the distant metastasis of colorectal cancer by inhibiting SLC7A11- and FTL-mediated ferroptosis. (PMID:37682704)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	amer1	ENSDARG00000079624
mus_musculus	Amer1	ENSMUSG00000050332
rattus_norvegicus	Amer1	ENSRNOG00000007984

Paralogs (2): AMER2 (ENSG00000165566), AMER3 (ENSG00000178171)

Protein

Protein identifiers

APC membrane recruitment protein 1 — Q5JTC6 (reviewed: Q5JTC6)

Alternative names: Protein FAM123B, Wilms tumor gene on the X chromosome protein

All UniProt accessions (1): Q5JTC6

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of the canonical Wnt signaling pathway. Acts by specifically binding phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), translocating to the cell membrane and interacting with key regulators of the canonical Wnt signaling pathway, such as components of the beta-catenin destruction complex. Acts both as a positive and negative regulator of the Wnt signaling pathway, depending on the context: acts as a positive regulator by promoting LRP6 phosphorylation. Also acts as a negative regulator by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the cell membrane. Promotes CTNNB1 ubiquitination and degradation. Involved in kidney development.

Subunit / interactions. Interacts with CTNNB1, AXIN1, LRP6, KEAP1, APC and BTRC. Interacts with SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes containing BTRC and/or FBXW11. Identified in the beta-catenin destruction complex containing CTNNB1, APC, AXIN1 and AXIN2. Interacts with WT1.

Subcellular location. Cytoplasm. Cell membrane. Nucleus.

Tissue specificity. Detected in fetal and adult kidney, brain and spleen.

Disease relevance. Osteopathia striata with cranial sclerosis (OSCS) [MIM:300373] An X-linked dominant sclerosing bone dysplasia that presents in females with macrocephaly, cleft palate, facial palsy, conductive hearing loss, mild learning disabilities, sclerosis of the long bones and skull. Longitudinal striations are visible on radiographs of the long bones, pelvis, and scapulae (osteopathia striata). In males this entity is usually associated with fetal or neonatal lethality. Occasional surviving males have, in addition to hyperostosis, cardiac, intestinal, and genitourinary malformations. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Inactivated in approximately one-third of Wilms tumors.

Similarity. Belongs to the Amer family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5JTC6-1	1, Amer1-S1	yes
Q5JTC6-2	2, Amer1-S2, Short

RefSeq proteins (1): NP_689637* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019003	AMER	Family

Pfam: PF09422

UniProt features (38 total): compositionally biased region 14, region of interest 7, mutagenesis site 7, sequence variant 4, modified residue 2, splice variant 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4YK6	X-RAY DIFFRACTION	1.7
4YJE	X-RAY DIFFRACTION	1.9
4YJL	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5JTC6-F1	48.88	0.08

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 1, 246

Mutagenesis-validated functional residues (7):

Position	Phenotype
54	abolishes interaction with ptdins(4,5)p2 and cell membrane localization; when associated with a-58; a-79; a-83; a-166; a
58	abolishes interaction with ptdins(4,5)p2 and cell membrane localization; when associated with a-54; a-79; a-83; a-166; a
79	abolishes interaction with ptdins(4,5)p2 and cell membrane localization; when associated with a-54; a-58; a-83; a-166; a
83	abolishes interaction with ptdins(4,5)p2 and cell membrane localization; when associated with a-54; a-58; a-79; a-166; a
166	abolishes interaction with ptdins(4,5)p2 and cell membrane localization; when associated with a-54; a-58; a-79; a-83; a-
181	abolishes interaction with ptdins(4,5)p2 and cell membrane localization; when associated with a-54; a-58; a-79; a-83; a-
183	abolishes interaction with ptdins(4,5)p2 and cell membrane localization; when associated with a-54; a-58; a-79; a-83; a-

Function

Pathways and Gene Ontology

Reactome pathways

29 pathways

ID	Pathway
R-HSA-195253	Degradation of beta-catenin by the destruction complex
R-HSA-196299	Beta-catenin phosphorylation cascade
R-HSA-4641262	Disassembly of the destruction complex and recruitment of AXIN to the membrane
R-HSA-5339716	Signaling by GSK3beta mutants
R-HSA-5358747	CTNNB1 S33 mutants aren’t phosphorylated
R-HSA-5358749	CTNNB1 S37 mutants aren’t phosphorylated
R-HSA-5358751	CTNNB1 S45 mutants aren’t phosphorylated
R-HSA-5358752	CTNNB1 T41 mutants aren’t phosphorylated
R-HSA-5467337	APC truncation mutants have impaired AXIN binding
R-HSA-5467340	AXIN missense mutants destabilize the destruction complex
R-HSA-5467348	Truncations of AMER1 destabilize the destruction complex
R-HSA-8951664	Neddylation
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-2262752	Cellular responses to stress
R-HSA-392499	Metabolism of proteins
R-HSA-4791275	Signaling by WNT in cancer
R-HSA-4839735	Signaling by AXIN mutants
R-HSA-4839743	Signaling by CTNNB1 phospho-site mutants
R-HSA-4839744	Signaling by APC mutants
R-HSA-4839748	Signaling by AMER1 mutants
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-597592	Post-translational protein modification
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9711123	Cellular response to chemical stress
R-HSA-5467343	Deletions in the AMER1 gene destabilize the destruction complex

MSigDB gene sets: 421 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, SP3_Q3, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, TGACCTY_ERR1_Q2, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, GOBP_BONE_DEVELOPMENT, SOX9_B1, GOBP_MESENCHYMAL_CELL_DIFFERENTIATION, GOBP_CELL_DIFFERENTIATION_INVOLVED_IN_KIDNEY_DEVELOPMENT, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY

GO Biological Process (10): Wnt signaling pathway (GO:0016055), positive regulation of protein ubiquitination (GO:0031398), positive regulation of protein catabolic process (GO:0045732), bone development (GO:0060348), adipose tissue development (GO:0060612), regulation of canonical Wnt signaling pathway (GO:0060828), mesenchymal cell differentiation involved in kidney development (GO:0072161), negative regulation of canonical Wnt signaling pathway (GO:0090090), positive regulation of canonical Wnt signaling pathway (GO:0090263), kidney development (GO:0001822)

GO Molecular Function (5): phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), beta-catenin binding (GO:0008013), beta-catenin destruction complex binding (GO:1904713), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (6): cytosol (GO:0005829), plasma membrane (GO:0005886), nuclear body (GO:0016604), nucleus (GO:0005634), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Signaling by CTNNB1 phospho-site mutants	4
Signaling by WNT	2
Degradation of beta-catenin by the destruction complex	1
TCF dependent signaling in response to WNT	1
Signaling by WNT in cancer	1
Signaling by APC mutants	1
Signaling by AXIN mutants	1
Signaling by AMER1 mutants	1
Post-translational protein modification	1
Cellular response to chemical stress	1
Signal Transduction	1
Cellular responses to stimuli	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
animal organ development	3
canonical Wnt signaling pathway	3
cellular anatomical structure	3
regulation of canonical Wnt signaling pathway	2
binding	2
cell surface receptor signaling pathway	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
skeletal system development	1
connective tissue development	1
regulation of Wnt signaling pathway	1
kidney development	1
mesenchymal cell differentiation	1
cell differentiation involved in kidney development	1
kidney mesenchyme development	1
negative regulation of Wnt signaling pathway	1
positive regulation of Wnt signaling pathway	1
renal system development	1
phosphatidylinositol phosphate binding	1
phosphatidylinositol bisphosphate binding	1
protein binding	1
protein-containing complex binding	1
cytoplasm	1
membrane	1
cell periphery	1
nucleoplasm	1
intracellular membraneless organelle	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

835 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AMER1	AXIN1	O15169	995
AMER1	GSK3B	P49841	969
AMER1	KEAP1	Q14145	909
AMER1	WT1	P19544	849
AMER1	CTNNB1	P35222	834
AMER1	CSNK1A1	P48729	812
AMER1	BTRC	Q9Y297	764
AMER1	POU6F2	P78424	740
AMER1	APC	P25054	732
AMER1	DPP3	Q9NY33	670
AMER1	AXIN2	Q9Y2T1	663
AMER1	DVL1	O14640	579
AMER1	GPC3	P51654	555
AMER1	ARID1A	O14497	544
AMER1	TP53	P04637	507

IntAct

91 interactions, top by confidence:

A	B	Type	Score
CTNNB1	AXIN1	psi-mi:“MI:0914”(association)	0.940
AXIN1	APC	psi-mi:“MI:0914”(association)	0.850
AMER1	APC	psi-mi:“MI:0915”(physical association)	0.720
AMER1	CTNNB1	psi-mi:“MI:0914”(association)	0.710
AMER1	CTNNB1	psi-mi:“MI:0915”(physical association)	0.710
AMER1	CTNNB1	psi-mi:“MI:0407”(direct interaction)	0.710
AMER1	AXIN1	psi-mi:“MI:0915”(physical association)	0.710
AMER1	FBXW11	psi-mi:“MI:0915”(physical association)	0.710
AMER1	BTRC	psi-mi:“MI:0915”(physical association)	0.690
AMER1	BTRC	psi-mi:“MI:0407”(direct interaction)	0.690
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
AMER3	APC	psi-mi:“MI:0914”(association)	0.630
CTNNB1	JUP	psi-mi:“MI:0914”(association)	0.610
AMER1	AMER3	psi-mi:“MI:0915”(physical association)	0.540
AMER1	AMER3	psi-mi:“MI:0403”(colocalization)	0.540
AMER3	AMER1	psi-mi:“MI:0915”(physical association)	0.540
FRMD1	A2ML1	psi-mi:“MI:0914”(association)	0.530
TSPYL6	NME4	psi-mi:“MI:0914”(association)	0.530
CPA6	PPM1G	psi-mi:“MI:0914”(association)	0.530
TSPYL1	GPC3	psi-mi:“MI:0914”(association)	0.530

BioGRID (100): AMER1 (Affinity Capture-MS), AMER1 (Affinity Capture-MS), AMER1 (Affinity Capture-MS), AMER1 (Affinity Capture-MS), AMER1 (Affinity Capture-MS), AMER1 (Affinity Capture-MS), AMER1 (Affinity Capture-MS), AMER1 (Affinity Capture-MS), AMER1 (Proximity Label-MS), AMER1 (Biochemical Activity), AMER1 (Affinity Capture-MS), AMER1 (Affinity Capture-MS), AMER1 (Affinity Capture-MS), AMER1 (Affinity Capture-MS), AMER1 (Affinity Capture-MS)

ESM2 similar proteins: A2A7Y5, A2A9F4, A2ALU4, A2RU30, A2VE02, A6NGG8, A6NMK8, B1AXH1, B2RQL2, D2J0Y4, M3WHG5, Q08DN6, Q0VET5, Q14B48, Q2NL68, Q2YDE2, Q4V8B5, Q5DTX6, Q5JTC6, Q5JXC2, Q5RCQ2, Q5SX79, Q5XIK6, Q66JV7, Q6AY88, Q6AYH0, Q6GQV1, Q6NS69, Q6P1D7, Q6PAC4, Q6ZRS4, Q76N32, Q7TP36, Q7TSA6, Q7Z591, Q80VW7, Q811R2, Q86YN6, Q8BP99, Q8C0C4

Diamond homologs: E1C2Q8, F1RDM5, Q5JTC6, Q6NS69, Q7TS75, Q8CCJ4, Q8N7J2, Q8N944

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
AMER1	“up-regulates activity”	AXIN1	relocalization
AMER1	up-regulates	CSNK1G1	binding
AMER1	“up-regulates activity”	GSK3B	relocalization
AMER1	up-regulates	WT1	binding
AMER1	up-regulates	APC	relocalization
AMER1	“down-regulates activity”	CTNNB1	binding
AMER1	“up-regulates activity”	GSK3B/Axin/APC	relocalization
AMER1	“up-regulates activity”	LRP6	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 76 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Degradation of beta-catenin by the destruction complex	5	19.2×	2e-03
Regulation of PLK1 Activity at G2/M Transition	5	14.1×	2e-03
TCF dependent signaling in response to WNT	5	13.1×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of canonical Wnt signaling pathway	7	12.3×	1e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 4 cancer types — COAD, COADREAD, READ, WT.

Clinical variants and AI predictions

ClinVar

672 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	37
Likely pathogenic	10
Uncertain significance	328
Likely benign	138
Benign	68

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
10704	NM_152424.4(AMER1):c.671del (p.Pro224fs)	Pathogenic
10705	NM_152424.4(AMER1):c.780dup (p.Pro261fs)	Pathogenic
10707	NM_152424.4(AMER1):c.1057C>T (p.Arg353Ter)	Pathogenic
10708	NM_152424.4(AMER1):c.1072C>T (p.Arg358Ter)	Pathogenic
1219202	NM_152424.4(AMER1):c.867_868del (p.Lys292fs)	Pathogenic
1323110	NM_152424.4(AMER1):c.179_180del (p.Phe60fs)	Pathogenic
1323114	NM_152424.4(AMER1):c.1000G>T (p.Glu334Ter)	Pathogenic
1408152	NM_152424.4(AMER1):c.372del (p.Cys125fs)	Pathogenic
1454631	NM_152424.4(AMER1):c.1180G>T (p.Glu394Ter)	Pathogenic
1457341	NM_152424.4(AMER1):c.376C>T (p.Gln126Ter)	Pathogenic
265617	NM_152424.4(AMER1):c.1243_1259del (p.Met415fs)	Pathogenic
2744814	NM_152424.4(AMER1):c.943del (p.Asp315fs)	Pathogenic
2745415	NM_152424.4(AMER1):c.645del (p.Cys216fs)	Pathogenic
29979	NM_152424.4(AMER1):c.429T>A (p.Cys143Ter)	Pathogenic
3062083	NM_152424.4(AMER1):c.877del (p.Lys292_Val293insTer)	Pathogenic
3377319	NM_152424.4(AMER1):c.694del (p.Gln232fs)	Pathogenic
37045	NM_152424.4(AMER1):c.1267del (p.Leu423fs)	Pathogenic
37046	NM_152424.4(AMER1):c.811C>T (p.Gln271Ter)	Pathogenic
379474	NM_152424.4(AMER1):c.571G>T (p.Glu191Ter)	Pathogenic
4091121	NM_152424.4(AMER1):c.1121T>A (p.Leu374Ter)	Pathogenic
429881	NM_152424.4(AMER1):c.705del (p.Pro237fs)	Pathogenic
4710852	NM_152424.4(AMER1):c.1003C>T (p.Gln335Ter)	Pathogenic
4713301	NM_152424.4(AMER1):c.992_996del (p.Ile331fs)	Pathogenic
4813475	NM_152424.4(AMER1):c.310del (p.His104fs)	Pathogenic
58638	GRCh38/hg38 Xp11.21-q11.2(chrX:55895084-65038751)x2	Pathogenic
58639	GRCh38/hg38 Xq11.1-13.1(chrX:62712219-71136309)x2	Pathogenic
636242	NM_152424.4(AMER1):c.565C>T (p.Gln189Ter)	Pathogenic
689241	GRCh37/hg19 Xq11.1-13.1(chrX:61882086-69173640)x1	Pathogenic
817104	NM_152424.4(AMER1):c.1100_1101insC (p.Gly368fs)	Pathogenic
935942	NM_152424.4(AMER1):c.1441del (p.Asp481fs)	Pathogenic

SpliceAI

313 predictions. Top by Δscore:

Variant	Effect	Δscore
X:64193394:A:AC	acceptor_gain	0.9900
X:64193394:A:C	acceptor_gain	0.9900
X:64205480:AGTGC:A	donor_gain	0.9900
X:64205563:CGCTT:C	donor_loss	0.9900
X:64205564:GCTTA:G	donor_loss	0.9900
X:64205565:CTTAC:C	donor_loss	0.9900
X:64205566:TTA:T	donor_loss	0.9900
X:64205567:TAC:T	donor_loss	0.9900
X:64205568:A:AC	donor_gain	0.9900
X:64205568:A:T	donor_loss	0.9900
X:64205568:AC:A	donor_gain	0.9900
X:64205569:C:CC	donor_gain	0.9900
X:64205569:C:CG	donor_loss	0.9900
X:64205569:CC:C	donor_gain	0.9900
X:64205569:CCCAG:C	donor_gain	0.9900
X:64205589:AG:A	donor_gain	0.9900
X:64205589:AGC:A	donor_gain	0.9900
X:64190480:T:TA	donor_gain	0.9800
X:64193385:C:CC	acceptor_gain	0.9800
X:64205572:AG:A	donor_gain	0.9800
X:64205572:AGC:A	donor_gain	0.9800
X:64193383:GTC:G	acceptor_loss	0.9700
X:64193384:TCTG:T	acceptor_loss	0.9700
X:64193385:C:G	acceptor_loss	0.9700
X:64205390:AAGG:A	donor_gain	0.9700
X:64205590:G:C	donor_gain	0.9700
X:64193380:GGGGT:G	acceptor_gain	0.9600
X:64205462:CCG:C	donor_gain	0.9600
X:64205473:AGT:A	donor_gain	0.9600
X:64190510:T:TA	donor_gain	0.9500

AlphaMissense

7432 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:64192321:A:C	F322L	0.999
X:64192321:A:T	F322L	0.999
X:64192323:A:G	F322L	0.999
X:64192194:A:C	Y365D	0.998
X:64190860:A:C	F809L	0.996
X:64190860:A:T	F809L	0.996
X:64190862:A:G	F809L	0.996
X:64192194:A:G	Y365H	0.996
X:64192322:A:G	F322S	0.996
X:64192324:G:C	S321R	0.996
X:64192324:G:T	S321R	0.996
X:64192326:T:G	S321R	0.996
X:64192194:A:T	Y365N	0.995
X:64192301:C:A	G329V	0.995
X:64192322:A:C	F322C	0.995
X:64190861:A:G	F809S	0.994
X:64190959:G:C	F776L	0.994
X:64190959:G:T	F776L	0.994
X:64190961:A:G	F776L	0.994
X:64192172:A:G	M372T	0.994
X:64192295:A:T	I331K	0.994
X:64192298:T:A	D330V	0.994
X:64192298:T:G	D330A	0.994
X:64192188:C:G	G367R	0.993
X:64192188:C:T	G367R	0.993
X:64192206:A:G	C361R	0.993
X:64192299:C:G	D330H	0.993
X:64192301:C:T	G329D	0.993
X:64192319:T:A	D323V	0.993
X:64192327:T:A	K320N	0.993

dbSNP variants (sampled 300 via entrez): RS1000032333 (X:64195366 C>T), RS1000233271 (X:64199399 T>C), RS1000388210 (X:64191700 A>G), RS1000583847 (X:64198932 A>T), RS1000655470 (X:64205552 G>A), RS1000657023 (X:64207329 T>C), RS1000725392 (X:64205896 C>A,T), RS1000884700 (X:64196783 T>C), RS1000983513 (X:64186286 A>G), RS1001014337 (X:64186697 C>T), RS1001530651 (X:64206302 C>G,T), RS1001540369 (X:64206644 C>G), RS1001706502 (X:64190286 T>A), RS1001743853 (X:64198768 G>C), RS1001939209 (X:64206503 G>A)

Disease associations

OMIM: gene MIM:300647 | disease phenotypes: MIM:300373, MIM:114500, MIM:300607

GenCC curated gene-disease

Disease	Classification	Inheritance
osteopathia striata with cranial sclerosis	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
osteopathia striata with cranial sclerosis	Definitive	XL

Mondo (7): osteopathia striata with cranial sclerosis (MONDO:0010310), colorectal cancer (MONDO:0005575), intellectual disability (MONDO:0001071), developmental and epileptic encephalopathy, 8 (MONDO:0010375), myocarditis (MONDO:0004496), obesity disorder (MONDO:0011122), cleft palate (MONDO:0016064)

Orphanet (8): Osteopathia striata-cranial sclerosis syndrome (Orphanet:2780), Hyperekplexia-epilepsy syndrome (Orphanet:163985), X-linked intellectual disability-epilepsy syndrome (Orphanet:2076), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Cleft palate (Orphanet:2014), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

100 total (30 of 100 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000179	Thick lower lip vermilion
HP:0000193	Bifid uvula
HP:0000201	Pierre-Robin sequence
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000239	Large fontanelles
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000270	Delayed cranial suture closure
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000396	Overfolded helix
HP:0000405	Conductive hearing impairment
HP:0000431	Wide nasal bridge
HP:0000465	Webbed neck
HP:0000518	Cataract
HP:0000678	Dental crowding
HP:0000684	Delayed eruption of teeth
HP:0000689	Dental malocclusion
HP:0000695	Natal tooth
HP:0000750	Delayed speech and language development

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009205	Myocarditis	C14.280.238.625
C564474	Hyperekplexia and Epilepsy (supp.)
C536053	Osteopathia striata cranial sclerosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	4
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases mutagenesis	2
Cisplatin	increases expression, decreases expression	2
Estradiol	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
azoxystrobin	decreases expression	1
deguelin	decreases expression	1
entinostat	decreases expression	1
fenpyroximate	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
pyrimidifen	decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
pyrachlostrobin	decreases expression	1
picoxystrobin	decreases expression	1
Leflunomide	decreases expression	1
Antimycin A	decreases expression	1
Arsenic	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Dactinomycin	affects cotreatment, increases expression	1
Diazinon	increases methylation	1
Methapyrilene	increases methylation	1

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00114829	PHASE4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	PHASE4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	PHASE4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	PHASE4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00129870	PHASE4	TERMINATED	CONCEPT: Comparison of Oxaliplatin vs Conventional Methods With Calcium/Magnesium in First-Line Metastatic Colorectal Cancer
NCT00138060	PHASE4	COMPLETED	Toxicity/Benefit Ratio Optimization of Chemotherapy in Colorectal Cancer (CRC) Patients by Determination of Individual Genotypic Determinants
NCT00216424	PHASE4	TERMINATED	Capecitabine (Xeloda) and Radiation for Patients With Rectosigmoid Carcinoma
NCT00327093	PHASE4	TERMINATED	Elaboration of a Model for Predicting Efficacy of Monoclonal Antibodies (Cetuximab and Bevacizumab) in Patients With Colorectal Cancer and Liver Metastases
NCT00332943	PHASE4	COMPLETED	MR Colonography With Fecal Tagging. Barium vs. BariumFerumoxsil
NCT00441311	PHASE4	COMPLETED	Dissemination of Colorectal Cancer Screening to Primary Care Physicians
NCT00460837	PHASE4	WITHDRAWN	Comparison of Bowel Preparation in Virtual Colonoscopy (VC) - Patient Experience
NCT00473980	PHASE4	COMPLETED	Preoperative Non-steroidal Anti-inflammatory Drugs(NSAID) to Colorectal Cancer Patients
NCT00488904	PHASE4	COMPLETED	Omega-3 Fatty Acids and Postoperative Complications After Colorectal Surgery
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00502671	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) as Adjuvant Monotherapy in Patients With Colon Cancer.
NCT00559676	PHASE4	COMPLETED	Study of Biomarkers in Patients Undergoing Chemotherapy for Metastatic Colorectal Cancer
NCT00577031	PHASE4	COMPLETED	OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.
NCT00626054	PHASE4	COMPLETED	Comparison of Two Methods of Administration of a PEG Solution
NCT00812864	PHASE4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00868569	PHASE4	UNKNOWN	Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer
NCT00868816	PHASE4	COMPLETED	Oxaliplatine Based Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: 8 Cycles Versus 12 Cycles
NCT00874406	PHASE4	UNKNOWN	Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer
NCT00928928	PHASE4	COMPLETED	Oxidative Stress Markers in Open and Laparoscopic Colectomy for Cancer
NCT00942461	PHASE4	COMPLETED	Inflammatory Response in Laparoscopic and Open Colectomy
NCT01023633	PHASE4	UNKNOWN	OPTIMOX1 in Chinese mCRC Patients
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01315990	PHASE4	UNKNOWN	FOLFIRI in Combination With Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer Including a Regular Dermal Prophylaxis to Prevent Acneiforme Follicular Exanthema
NCT01493713	PHASE4	COMPLETED	Correlation Between RECIST, Morphologic Response by CT- Histopathologic Response in Hepatic Metastasis Secondary to Colorectal Cancer
NCT01609660	PHASE4	COMPLETED	Impact of Probiotics on the Intestinal Microbiota
NCT01641458	PHASE4	COMPLETED	Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
NCT01689792	PHASE4	COMPLETED	A Multi-centre Study Comparing the Polyp Detection Rate of Two Different Types of Bowel Preparation: a 2-litre Solution (MOVIPREP®) Versus a Hyperosmotic and Stimulant Combined Low Volume Bowel Preparation (Sodium Picosulfate and Magnesium Citrate)
NCT01695772	PHASE4	COMPLETED	A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer
NCT01695863	PHASE4	COMPLETED	Efficacy and Patient Satisfaction of Miralax and Gatorade Versus Movi Prep
NCT01706822	PHASE4	TERMINATED	Radial Reload Laparoscopic LAR Case Series
NCT01740947	PHASE4	TERMINATED	Does Administration of Antibiotics in Patients Undergoing Surgery for Colorectal Cancer Result in Less Complications and Better Prognosis?
NCT01831310	PHASE4	COMPLETED	Nutrition for Colorectal Cancer Patients and Neutrophil Functions
NCT01841294	PHASE4	UNKNOWN	NK Activity Modulation Induced by Intravenous Lidocaine During Colorectal Laparoscopic Surgery
NCT01959061	PHASE4	UNKNOWN	Efficacy and Safety of Raltitrexed-based Transarterial Chemoembolisation(TACE)for Colorectal Cancer Liver Metastases
NCT02032953	PHASE4	UNKNOWN	Enhancing the Anabolic Effect of Perioperative Nutrition With Insulin While Maintaining Normoglycemia
NCT02567331	PHASE4	COMPLETED	A Study of Capecitabine (Xeloda) in Patients With Metastatic Colorectal Cancer