ITM2B

Summary

ITM2B (integral membrane protein 2B, HGNC:6174) is a protein-coding gene on chromosome 13q14.2, encoding Integral membrane protein 2B (Q9Y287). Plays a regulatory role in the processing of the amyloid-beta A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta peptide aggregation and fibrils deposition.

Amyloid precursor proteins are processed by beta-secretase and gamma-secretase to produce beta-amyloid peptides which form the characteristic plaques of Alzheimer disease. This gene encodes a transmembrane protein which is processed at the C-terminus by furin or furin-like proteases to produce a small secreted peptide which inhibits the deposition of beta-amyloid. Mutations which result in extension of the C-terminal end of the encoded protein, thereby increasing the size of the secreted peptide, are associated with two neurogenerative diseases, familial British dementia and familial Danish dementia.

Source: NCBI Gene 9445 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ABri amyloidosis (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 194 total — 11 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 22
• MANE Select transcript: NM_021999

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6174
Approved symbol	ITM2B
Name	integral membrane protein 2B
Location	13q14.2
Locus type	gene with protein product
Status	Approved
Aliases	BRI, E25B, E3-16, BRICD2B, BRI2
Ensembl gene	ENSG00000136156
Ensembl biotype	protein_coding
OMIM	603904
Entrez	9445

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 9 protein_coding, 4 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000378549, ENST00000463839, ENST00000607866, ENST00000647800, ENST00000648312, ENST00000648586, ENST00000648898, ENST00000649266, ENST00000649452, ENST00000650237, ENST00000650479, ENST00000899431, ENST00000899432, ENST00000899433, ENST00000970637, ENST00000970638

RefSeq mRNA: 1 — MANE Select: NM_021999 NM_021999

CCDS: CCDS9409

Canonical transcript exons

ENST00000647800 — 6 exons

Exon	Start	End
ENSE00000923441	48253808	48253936
ENSE00000923442	48256177	48256383
ENSE00000923443	48258126	48258236
ENSE00000923444	48258797	48258947
ENSE00001533067	48261139	48270357
ENSE00003840816	48233206	48233477

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 524.6465 / max 12720.7945, expressed in 1827 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
135044	330.5614	1824
135043	118.2418	1819
135042	47.3758	1819
135045	14.5156	1722
135046	6.1498	1529
135049	3.0149	1252
135050	2.3835	1152
135048	2.0524	977
135047	0.1718	75
135039	0.0739	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal glomerulus	UBERON:0000074	99.95	gold quality
metanephric glomerulus	UBERON:0004736	99.95	gold quality
germinal epithelium of ovary	UBERON:0001304	99.94	gold quality
corpus epididymis	UBERON:0004359	99.94	gold quality
kidney epithelium	UBERON:0004819	99.92	gold quality
adult organism	UBERON:0007023	99.92	gold quality
nephron tubule	UBERON:0001231	99.91	gold quality
metanephros	UBERON:0000081	99.90	gold quality
renal medulla	UBERON:0000362	99.90	gold quality
jejunal mucosa	UBERON:0000399	99.90	gold quality
visceral pleura	UBERON:0002401	99.90	gold quality
pleura	UBERON:0000977	99.89	gold quality
parietal pleura	UBERON:0002400	99.89	gold quality
pigmented layer of retina	UBERON:0001782	99.88	gold quality
caput epididymis	UBERON:0004358	99.88	gold quality
tibia	UBERON:0000979	99.85	gold quality
cortex of kidney	UBERON:0001225	99.85	gold quality
choroid plexus epithelium	UBERON:0003911	99.85	gold quality
cauda epididymis	UBERON:0004360	99.85	gold quality
metanephros cortex	UBERON:0010533	99.84	gold quality
seminal vesicle	UBERON:0000998	99.82	gold quality
gingival epithelium	UBERON:0001949	99.82	gold quality
kidney	UBERON:0002113	99.81	gold quality
synovial joint	UBERON:0002217	99.81	gold quality
placenta	UBERON:0001987	99.80	gold quality
adult mammalian kidney	UBERON:0000082	99.79	gold quality
gingiva	UBERON:0001828	99.79	gold quality
urethra	UBERON:0000057	99.78	gold quality
skin of hip	UBERON:0001554	99.78	gold quality
right lung	UBERON:0002167	99.78	gold quality

Single-cell (SCXA)

Detected in 45 experiment(s), a significant marker in 31.

Experiment	Marker?	Max mean expression
E-MTAB-6308	yes	9187.22
E-MTAB-6653	yes	8513.46
E-HCAD-15	yes	6735.19
E-GEOD-114530	yes	6636.92
E-HCAD-1	yes	3579.99
E-MTAB-10042	yes	3346.68
E-MTAB-11121	yes	2596.52
E-HCAD-10	yes	2087.47
E-HCAD-4	yes	1725.29
E-CURD-112	yes	1359.25
E-GEOD-111727	yes	1278.60
E-MTAB-8205	yes	1188.63
E-HCAD-8	yes	61.74
E-MTAB-8410	yes	51.85
E-MTAB-10553	yes	50.27

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

97 targeting ITM2B, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4803	99.98	71.99	3117
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-4760-3P	99.93	70.50	2385

Literature-anchored findings (GeneRIF, showing 40)

• oxidized form of ABri and reduced form of ADan are toxic to human neuronal cell lines in culture (PMID:12196136)
• Data show that the expression of BRI gene was up-regulated in the highly metastatic cell line and down-regulated in the low metastatic cell line and there was no relation between BRI gene differential expression and rearrangements of chromosome. (PMID:12903036)
• While a physiological role of BRI in brain remains to be determined, the behavior of BRI in diverse brain lesions appears to be somewhat analogous to that of amyloid precursor protein. (PMID:14586629)
• expression of wild-type British or Danish mutants of BRI2, in mouse neuroblastoma N2a cells that do not express endogenous BRI2, induces elongation of neurites, which suggests a role for this protein in differentiation of neuronal cells (PMID:14656991)
• Mutations at or near the stop codon of the chromosome 13 gene BRI2 that cause generation of longer-than-normal protein products. (PMID:15968464)
• BRI2 gene binds the Alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta production (PMID:15983050)
• BRI2 had a modulatory effect on amyloid precursor protein (APP) processing, increasing levels of cellular APP and COOH-terminal fragments while decreasing COOH-terminal fragments and secretion of total APP and Abeta peptides. (PMID:16027166)
• early-onset dementia is linked to specific mutations in the BRI2 {REVIEW} (PMID:16612984)
• SPPL2a and SPPL2b mediate the intramembrane cleavage, whereas neither SPP nor SPPL3 is capable of processing the Bri2 N-terminal fragment. (PMID:17965014)
• in familial British dementia the mutated precursor BRi2 protein may undergo furin cleavage within neurones to produce the amyloid peptide ABri (PMID:18282158)
• BRI2 dimerizes in cells and that dimers are held via non-covalent interactions and via disulfide bridges between the cysteines at position 89. Additionally, we showed that BRI2 dimers are formed in the ER and appear at the cell surface. (PMID:18440095)
• Expression of wild-type human ITM2B reduces cerebral amyloid beta deposition in a mouse model of Alzheimer’s disease. (PMID:18524908)
• BRI3 inhibits the various processing of amyloid protein precursor by blocking the access of alpha- and beta-secretases in a manner unlike BRI2. (PMID:19366692)
• BRI2 is a specific inhibitor that reduces access of secretase to amyloid-betaprecursor protein (APP) in intracellular compartments where APP is normally processed. (PMID:19748705)
• These data suggest a model for how the processing of Bri2 and APP are interrelated. (PMID:20036644)
• Decreased cerebrospinal fluid levels of Bri2-23, a peptide cleaved from Bri2, significantly associates with multiple scleerosis patients with cerebellar dysfunction and cognition impairment. (PMID:20600910)
• The British mutation drastically reduces expression of mature BRI2 in both knock-in mice and the brains of familial British dementia patients. (PMID:21048150)
• Knock-in mice with familial Danish dementia, a mouse model congruous to human disease since they carry one mutant and one wild-type Bri2 allele, show that the Danish mutation causes loss of Bri2 protein, synaptic plasticity and memory impairment. (PMID:21587206)
• BRI2 is N-glycosylated at Asn170 and show that this post-translational modification is essential for its expression at the cell surface but not for its proteolytic processing. (PMID:21752865)
• Neurological effects of the Danish form of BRI2 dementia caused by toxic amyloid Abeta protein precursor metabolites suggest that familial Danish and Alzheimer’s dementias share common pathogenic mechanisms. (PMID:21841249)
• BRI2 protein regulates beta-amyloid degradation by increasing levels of secreted insulin-degrading enzyme (IDE). (PMID:21873424)
• The alpha-helical content of the transmembrane domain of the British dementia protein-2 (Bri2) determines its processing by signal peptide peptidase-like 2b (SPPL2b). (PMID:22194595)
• Similarities of ABri and ADan to Abeta in Alzheimer’s disease suggest that posttranslational pGlu-modification of amyloid peptides might represent general pathological mechanism leading to increased aggregation and toxicity forms of degenerative dementias. (PMID:23261769)
• Data indicate that double transgenic (Tg-FDD-Tau) mice showed a significant decrease in synaptophysin levels. (PMID:23418567)
• These results suggest that BRI2 may prevent access of BACE1 to APP and the BRI2/BACE1 interaction may mediate the reduction in BACE1 levels. (PMID:23701002)
• Findings highlight pathogenic mechanism(s) associated with ITM2B mutations underlying dementia or retinal disease and add a new candidate to the list of genes involved in inherited retinal dystrophies. (PMID:24026677)
• Structural modeling of transmembrane (BRICHOS) domains of BRI2/ITM2B and SFTPC (pulmonary surfactant protein C) precursor identifies conserved region structurally complementary to beta-sheet/amyloid-prone region in BRICHOS domain-containing proteins. (PMID:24099305)
• This review support the hypothesis that BRI2 change during disease devel-opment, and thus may have a role in Alzheimer disease. (PMID:24473189)
• It binds amyloid precursor protein to halt amyloid-b production and inhibits amyloid-b aggregation via its BRICHOS-domain suggesting a link between BRI2 and Alzheimer’s disease (AD) (PMID:24524963)
• Data indicate that the mutation originates the highly amyloidogenic molecule integral membrane protein 2B ABri. (PMID:25261792)
• Data indicate integral membrane 2B (ITM2B) as a target of B-cell CLL/lymphoma 6 protein (BCL6) repression in lymphoma. (PMID:25557390)
• Cystine-linked oligomers of ABri are toxic to neurons and block long-term potentiation. (PMID:25957407)
• familial Danish dementia mutation and pE posttranslational modification are primary elements driving intact ADan into an amyloidogenic/neurotoxic pathway while truncations at the C-terminus eliminate the pro-amyloidogenic characteristics of the molecule (PMID:26459115)
• when BRI2 is phosphorylated a significant increase in neuronal outgrowth and differentiation is evident (PMID:26515131)
• Data depict roles for Bri2 and apolipoprotein E4 (ApoE4) proteins in a long-term memory regulation pathway. A single mutation in one Itm2b/Bri2 allele can affect both long-term and working memory, while ApoE4 seems to regulate short-term/working memory. (PMID:26528887)
• ITM2B is expressed in most cortical neurons, neurons of the hippocampus and dentate nucleus, cerebellar Purkinje and granule cells, and (newly described here) in focal neurons in the basal ganglia, many neurons of the thalamus and brainstem, many cells in the ependyma and choroid plexus, and in the smooth muscle of blood vessels. ITM2B expression is prominent in plaques in AD-containing dystrophic neurites (PMID:26862951)
• Familial British dementia (FBD) and familial Danish dementia (FDD) are caused by mutations in the BRI2 gene. (PMID:28131015)
• by modulating BRI2 processing using an ADAM10 inhibitor, a dual role for BRI2 in neurite outgrowth is suggested: phosphorylated full-length BRI2 appears to be important for the formation of neuritic processes, and BRI2 NTF promotes neurite elongation. (PMID:28176357)
• Bri2 BRICHOS monomers potently prevent neuronal network toxicity of amyloid-beta peptide (A-beta), while dimers strongly suppress A-beta fibril formation. (PMID:29234026)
• We found a novel possible pathogenic variant in the ITM2B gene in one amyotrophic lateral sclerosis patient with a complex phenotype, associating movement disorders, psychiatric and cognitive features, deafness, and optic atrophy. (PMID:29480190)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	itm2ba	ENSDARG00000007098
danio_rerio	itm2bb	ENSDARG00000041505
mus_musculus	Itm2b	ENSMUSG00000022108
rattus_norvegicus	Itm2b	ENSRNOG00000016271
drosophila_melanogaster	CG3662	FBGN0031285
caenorhabditis_elegans		WBGENE00016106

Paralogs (2): ITM2A (ENSG00000078596), ITM2C (ENSG00000135916)

Protein

Protein identifiers

Integral membrane protein 2B — Q9Y287 (reviewed: Q9Y287)

Alternative names: Immature BRI2, Protein E25B, Transmembrane protein BRI

All UniProt accessions (8): A0A384MDP7, Q9Y287, A0A3B3ISG3, A0A3B3ITP9, A0A3B3IU60, A0A3B3IUC0, U3KQ52, U3KQL7

UniProt curated annotations — full annotation on UniProt →

Function. Plays a regulatory role in the processing of the amyloid-beta A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta peptide aggregation and fibrils deposition. Plays a role in the induction of neurite outgrowth. Functions as a protease inhibitor by blocking access of secretases to APP cleavage sites. Mature BRI2 (mBRI2) functions as a modulator of the amyloid-beta A4 precursor protein (APP) processing leading to a strong reduction in the secretion of secretase-processed amyloid-beta protein 40 and amyloid-beta protein 42. Bri23 peptide prevents aggregation of APP amyloid-beta protein 42 into toxic oligomers.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with SPPL2A and SPPL2B. Interacts with APP. Mature BRI2 (mBRI2) interacts with the APP amyloid-beta A4 protein; the interaction occurs at the cell surface and in the endocytic compartments and enable alpha- and beta-secretase-induced APP cleavage inhibition. Mature BRI2 (mBRI2) interacts with the APP C99; the interaction occurs in the endocytic compartments and enable gamma-secretase-induced C99 cleavage inhibition. May form heterodimers with Bri23 peptide and APP amyloid-beta protein 40. Interacts with ADAM7 in sperm; the interaction increases following capacitation.

Subcellular location. Golgi apparatus membrane Cell membrane. Endosome membrane Secreted Secreted.

Tissue specificity. Ubiquitous. Expressed in brain.

Post-translational modifications. The ectodomain C-terminal part of the imBRI2 is processed by furin producing a secreted Bri23 peptide and a mature BRI2, membrane form (mBRI2). The remaining part of the ectodomain of mBRI2 containing the BRICHOS domain is cleaved by ADAM10 and is secreted (BRI2C, soluble form). The membrane-bound N-terminal fragment (BRI2C, membrane form) is further proteolytically processed by SPPL2A and SPPL2B through regulated intramembrane proteolysis producing a secreted C-peptide and a BRI2 intracellular domain (BRI2 ICD) released in the cytosol. Shedding by ADAM10 facilitates intramembrane cleavage but is not absolutely required for BRI2 ICD generation. Glycosylation at Asn-170 is important for cell surface localization, but doesn’t affect furin- and ADAM10-induced proteolytic processing.

Disease relevance. Cerebral amyloid angiopathy, ITM2B-related 1 (CAA-ITM2B1) [MIM:176500] A disorder characterized by amyloid deposition in the walls of cerebral blood vessels and neurodegeneration in the central nervous system. Cerebral amyloid angiopathy, non-neuritic and perivascular plaques and neurofibrillary tangles are the predominant pathological lesions. Clinical features include progressive mental deterioration, spasticity and muscular rigidity. The disease is caused by variants affecting the gene represented in this entry. A single base substitution at the stop codon of ITM2B generates a 277-residue precursor that is cleaved at the normal furin processing site to generate the ABri amyloidogenic peptide. ABri accumulates in the brain and produces amyloid fibrils responsible for neuronal dysfunction and dementia. ABri peptide variant forms fibrils in vitro. Cerebral amyloid angiopathy, ITM2B-related 2 (CAA-ITM2B2) [MIM:117300] A disorder characterized by amyloid deposition in the walls of the blood vessels of the cerebrum, choroid plexus, cerebellum, spinal cord and retina. Plaques and neurofibrillary tangles are observed in the hippocampus. Clinical features include progressive ataxia, dementia, cataracts and deafness. The disease is caused by variants affecting the gene represented in this entry. A decamer duplication in the 3’ region of ITM2B results in the production of the ADan amyloidogenic peptide. ADan is generated by cleavage of the mutated precursor at the normal furin processing site. ADan accumulates in the brain and produces amyloid fibrils responsible for neuronal dysfunction and dementia. Retinal dystrophy with inner retinal dysfunction and ganglion cell abnormalities (RDGCA) [MIM:616079] An autosomal dominant retinal dystrophy characterized by inner retinal dysfunction in association with ganglion cell abnormalities. Clinical features include mild photophobia, progressive loss of central vision, night blindness, and hyperreflectivity of nerve and ganglion cell layers. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ITM2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y287-1	1	yes
Q9Y287-2	2

RefSeq proteins (1): NP_068839* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007084	BRICHOS_dom	Domain
IPR040145	ITM2	Family

Pfam: PF04089

UniProt features (35 total): strand 7, chain 4, sequence variant 4, disulfide bond 3, mutagenesis site 3, turn 3, helix 2, topological domain 2, site 1, glycosylation site 1, splice variant 1, peptide 1, transmembrane region 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8RNU	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y287-F1	76.31	0.43

Functional residue map

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

Catalytic / active sites (1): 243–244 (cleavage; by furin)

Disulfide bonds (3): 89, 164–223, 248–265

Glycosylation sites (1): 170

Mutagenesis-validated functional residues (3):

Position	Phenotype
60	strongly reduces intramembrane cleavage by sppl2b.
170	accumulates in intracellular compartments. does not inhibit furin, adam10 and sppl2a extracellular proteolytic processin
243–244	inhibits cleavage by furin. does not prevent adam10 shedding.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-977225	Amyloid fiber formation
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 371 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, SHEPARD_BMYB_MORPHOLINO_UP, KAAB_FAILED_HEART_ATRIUM_DN, ENK_UV_RESPONSE_KERATINOCYTE_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOLDRATH_ANTIGEN_RESPONSE, GOBP_REGULATION_OF_GLYCOPROTEIN_METABOLIC_PROCESS, JOHANSSON_BRAIN_CANCER_EARLY_VS_LATE_DN, AP1_Q4_01, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_UP, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, LUI_TARGETS_OF_PAX8_PPARG_FUSION

GO Biological Process (2): nervous system development (GO:0007399), negative regulation of amyloid precursor protein biosynthetic process (GO:0042985)

GO Molecular Function (3): amyloid-beta binding (GO:0001540), ATP binding (GO:0005524), protein binding (GO:0005515)

GO Cellular Component (11): Golgi membrane (GO:0000139), extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), Golgi-associated vesicle membrane (GO:0030660), organelle membrane (GO:0031090), extracellular exosome (GO:0070062), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
bounding membrane of organelle	3
cellular anatomical structure	2
endomembrane system	2
membrane	2
cytoplasmic vesicle membrane	2
system development	1
negative regulation of glycoprotein biosynthetic process	1
amyloid precursor protein biosynthetic process	1
regulation of amyloid precursor protein biosynthetic process	1
peptide binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
binding	1
Golgi apparatus	1
cytoplasm	1
intracellular membrane-bounded organelle	1
cell periphery	1
endosome	1
Golgi-associated vesicle	1
membrane-bounded organelle	1
extracellular vesicle	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

1630 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ITM2B	APP	P05067	848
ITM2B	CST3	P01034	799
ITM2B	RCBTB2	O95199	629
ITM2B	SPPL2B	Q8TCT7	620
ITM2B	SPPL2A	Q8TCT8	586
ITM2B	LPAR6	P43657	560
ITM2B	BACE1	P56817	501
ITM2B	HM13	Q8TCT9	479
ITM2B	CNMD	O75829	474
ITM2B	CANX	P27824	464
ITM2B	MLNR	O43193	458
ITM2B	FNDC3A	Q9Y2H6	453
ITM2B	PHF11	Q9UIL8	452
ITM2B	PSEN1	P49768	445
ITM2B	CDADC1	Q9BWV3	444

IntAct

127 interactions, top by confidence:

A	B	Type	Score
ITM2B	APP	psi-mi:“MI:0915”(physical association)	0.770
APP	ITM2B	psi-mi:“MI:0915”(physical association)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ITM2B	TMEM59L	psi-mi:“MI:0915”(physical association)	0.620
ITM2B	NAALADL2	psi-mi:“MI:0915”(physical association)	0.560
SYNE4	ITM2B	psi-mi:“MI:0915”(physical association)	0.560
ITM2B	KASH5	psi-mi:“MI:0915”(physical association)	0.560
ITM2B	SYNE4	psi-mi:“MI:0915”(physical association)	0.560
KASH5	ITM2B	psi-mi:“MI:0915”(physical association)	0.560
NAALADL2	ITM2B	psi-mi:“MI:0915”(physical association)	0.560
ITM2B	BACE1	psi-mi:“MI:0915”(physical association)	0.560
ITM2B	BACE1	psi-mi:“MI:0403”(colocalization)	0.560
KLRC1	ITM2B	psi-mi:“MI:0915”(physical association)	0.560
RAB3C	ITM2B	psi-mi:“MI:0915”(physical association)	0.560
CREB3	ITM2B	psi-mi:“MI:0915”(physical association)	0.550
ITM2B	SLC2A9	psi-mi:“MI:0915”(physical association)	0.540

BioGRID (160): CCDC155 (Two-hybrid), SYNE4 (Two-hybrid), NAALADL2 (Two-hybrid), HLA-A (Affinity Capture-MS), UBR1 (Affinity Capture-MS), DCBLD2 (Affinity Capture-MS), MR1 (Affinity Capture-MS), BTN2A2 (Affinity Capture-MS), SEMA4F (Affinity Capture-MS), ATF6B (Affinity Capture-MS), CHST12 (Affinity Capture-MS), TMEM59L (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), HS6ST1 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS)

ESM2 similar proteins: A2VDN0, A5A6H8, B5DFM7, E9Q9F6, O18638, O42204, O43736, O88393, O89051, P0DP43, P21841, P26342, P58239, Q03167, Q06890, Q06AV4, Q14CH0, Q29TV8, Q3T0P7, Q4R540, Q52N47, Q5NVC3, Q5PQL7, Q5R876, Q5SC59, Q5SC60, Q5SY80, Q5XIE8, Q60HC1, Q61500, Q6AYE5, Q6GPK2, Q6P7C7, Q6P995, Q6W3E5, Q71SY6, Q802A9, Q86XM0, Q86XP6, Q8BGN6

Diamond homologs: A2VDN0, A5A6H8, O42204, O43736, O89051, Q06AV4, Q3T0P7, Q4R540, Q52N47, Q5NVC3, Q5PQL7, Q5R876, Q5XIE8, Q60HC1, Q61500, Q91VK4, Q9NQX7, Q9Y287

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 128 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
NCAM signaling for neurite out-growth	6	21.8×	3e-05
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	7	8.1×	8e-04

GO biological processes:

GO term	Partners	Fold	FDR
immune response	12	5.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	1
Uncertain significance	113
Likely benign	51
Benign	4

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1074926	NC_000013.10:g.(?48611883)(48939117_?)del	Pathogenic
1459011	NC_000013.10:g.(?48611883)(48878195_?)del	Pathogenic
157606	NM_021999.5(ITM2B):c.782A>C (p.Glu261Ala)	Pathogenic
2572169	NC_000013.11:g.48194644_48318494del	Pathogenic
3244121	NC_000013.10:g.(?48611883)(48955589_?)del	Pathogenic
3244122	NC_000013.10:g.(?48517506)(49039524_?)del	Pathogenic
442778	GRCh37/hg19 13q14.2(chr13:48756523-48899280)x1	Pathogenic
5979	NM_021999.5(ITM2B):c.799T>A (p.Ter267Arg)	Pathogenic
5980	NM_021999.5(ITM2B):c.787_796dup (p.Ser266fs)	Pathogenic
830876	NC_000013.11:g.(?48037747)(48480071_?)del	Pathogenic
832661	NC_000013.11:g.(?48040910)(48480071_?)del	Pathogenic
1334024	NM_021999.5(ITM2B):c.800G>T (p.Ter267Leu)	Likely pathogenic

SpliceAI

998 predictions. Top by Δscore:

Variant	Effect	Δscore
13:48233433:G:GT	donor_gain	1.0000
13:48233500:G:GT	donor_gain	1.0000
13:48253804:TTA:T	acceptor_loss	1.0000
13:48253806:A:AG	acceptor_gain	1.0000
13:48253807:G:GC	acceptor_loss	1.0000
13:48253807:G:GG	acceptor_gain	1.0000
13:48253932:TTCAA:T	donor_gain	1.0000
13:48253934:CAAG:C	donor_loss	1.0000
13:48253935:AAG:A	donor_loss	1.0000
13:48253936:AGT:A	donor_loss	1.0000
13:48253937:G:GG	donor_gain	1.0000
13:48253938:TAAGT:T	donor_loss	1.0000
13:48256173:ATAG:A	acceptor_loss	1.0000
13:48256174:T:G	acceptor_gain	1.0000
13:48256174:TAGC:T	acceptor_loss	1.0000
13:48256175:A:AG	acceptor_gain	1.0000
13:48256175:A:T	acceptor_loss	1.0000
13:48256176:G:GT	acceptor_gain	1.0000
13:48256176:GC:G	acceptor_gain	1.0000
13:48256176:GCC:G	acceptor_gain	1.0000
13:48256176:GCCA:G	acceptor_gain	1.0000
13:48256382:AGGTG:A	donor_loss	1.0000
13:48258788:T:A	acceptor_gain	1.0000
13:48258792:TGTA:T	acceptor_loss	1.0000
13:48258793:GTAG:G	acceptor_loss	1.0000
13:48258794:TA:T	acceptor_loss	1.0000
13:48258795:A:AG	acceptor_gain	1.0000
13:48258795:A:C	acceptor_loss	1.0000
13:48258795:AG:A	acceptor_gain	1.0000
13:48258796:G:GT	acceptor_gain	1.0000

AlphaMissense

1769 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:48258162:T:A	C164S	1.000
13:48258162:T:C	C164R	1.000
13:48258163:G:C	C164S	1.000
13:48258164:C:G	C164W	1.000
13:48258899:T:A	C223S	1.000
13:48258900:G:C	C223S	1.000
13:48258901:T:G	C223W	1.000
13:48256367:T:A	V146D	0.999
13:48256369:C:G	H147D	0.999
13:48256375:T:C	F149L	0.999
13:48256376:T:G	F149C	0.999
13:48256377:T:A	F149L	0.999
13:48256377:T:G	F149L	0.999
13:48258130:T:C	L153P	0.999
13:48258133:C:T	T154I	0.999
13:48258135:G:C	A155P	0.999
13:48258136:C:A	A155D	0.999
13:48258138:T:G	Y156D	0.999
13:48258163:G:A	C164Y	0.999
13:48258163:G:T	C164F	0.999
13:48258178:T:C	L169P	0.999
13:48258899:T:C	C223R	0.999
13:48258900:G:A	C223Y	0.999
13:48258924:T:C	L231P	0.999
13:48253869:G:A	G60E	0.998
13:48256340:T:G	F137C	0.998
13:48256364:T:A	I145N	0.998
13:48256364:T:G	I145S	0.998
13:48256370:A:C	H147P	0.998
13:48256371:T:A	H147Q	0.998

dbSNP variants (sampled 300 via entrez): RS1000166839 (13:48252081 T>C), RS1000205858 (13:48235251 C>T), RS1000211186 (13:48241473 A>G), RS1000372529 (13:48246365 C>A), RS1000494963 (13:48259254 G>A), RS1000498979 (13:48234979 A>G), RS1000500679 (13:48234055 G>A), RS1000550831 (13:48253029 G>A), RS1000580818 (13:48257189 C>A), RS1000674000 (13:48245195 A>C,G,T), RS1000771314 (13:48251307 T>C), RS1000774390 (13:48247075 C>T), RS1000971800 (13:48265808 A>C), RS1001111171 (13:48244992 C>A,G), RS1001204051 (13:48259071 A>C,G)

Disease associations

OMIM: gene MIM:603904 | disease phenotypes: MIM:176500, MIM:117300, MIM:616079

GenCC curated gene-disease

Disease	Classification	Inheritance
ABri amyloidosis	Strong	Autosomal dominant
retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies	Supportive	Autosomal dominant
ADan amyloidosis	Supportive	Autosomal dominant

Mondo (7): retinoblastoma (MONDO:0008380), ABri amyloidosis (MONDO:0008306), ADan amyloidosis (MONDO:0007297), retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies (MONDO:0014483), optic atrophy (MONDO:0003608), hereditary ataxia (MONDO:0100309), vascular dementia (MONDO:0004648)

Orphanet (6): Retinoblastoma (Orphanet:790), ITM2B amyloidosis (Orphanet:439254), ABri amyloidosis (Orphanet:97345), Retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies (Orphanet:397758), ADan amyloidosis (Orphanet:97346), Hereditary ataxia (Orphanet:183518)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000365	Hearing impairment
HP:0000543	Optic disc pallor
HP:0000556	Retinal dystrophy
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000662	Nyctalopia
HP:0000709	Psychosis
HP:0000726	Dementia
HP:0001115	Posterior polar cataract
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001276	Hypertonia
HP:0001337	Tremor
HP:0002063	Rigidity
HP:0002080	Intention tremor
HP:0002185	Neurofibrillary tangles
HP:0002344	Progressive neurologic deterioration
HP:0003596	Middle age onset
HP:0007663	Reduced visual acuity
HP:0011462	Young adult onset
HP:0011970	Cerebral amyloid angiopathy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90026413_7	Severe insulin-deficient type 2 diabetes	4.000000e-06

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D012175	Retinoblastoma	C04.557.465.625.600.725; C04.557.470.670.725; C04.557.580.625.600.725; C04.588.364.818.760; C11.270.862; C11.319.475.760; C11.768.717.760
C538209	Dementia, familial Danish (supp.)
C531684	Hereditary spinal ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	increases expression	4
sodium arsenite	affects cotreatment, increases expression	3
mercuric bromide	increases expression, affects cotreatment	2
chloropicrin	decreases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Cisplatin	increases expression, increases reaction	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Valproic Acid	increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
deoxynivalenol	decreases expression	1
lead acetate	affects cotreatment, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	decreases expression	1
nivalenol	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CD 437	decreases expression	1
corosolic acid	increases expression	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	increases expression, increases reaction	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	decreases ubiquitination	1

Cellosaurus cell lines

7 cell lines: 7 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C9J4	IDVi003-A-4	Induced pluripotent stem cell	Male
CVCL_C9J5	IDVi003-A-5	Induced pluripotent stem cell	Male
CVCL_C9J6	IDVi003-A-6	Induced pluripotent stem cell	Male
CVCL_E7NJ	KOLF2.1J ITM2B 28kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_XJ40	IDVi003-A	Induced pluripotent stem cell	Male
CVCL_XJ41	IDVi003-B	Induced pluripotent stem cell	Male
CVCL_XJ42	IDVi003-C	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00336531	PHASE4	COMPLETED	Efficacy of Prophylactic Itraconazole in High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation
NCT02319486	PHASE4	COMPLETED	CEV With/Without Periocular Carboplatin Chemotherapy for Extraocular Retinoblastoma
NCT02933333	PHASE4	UNKNOWN	G-CSF Alone or Combination With GM-CSF on Prevention and Treatment of Infection in Children With Malignant Tumor
NCT00186888	PHASE3	COMPLETED	Study of Treatment for Patients With Cancer of the Eye -Retinoblastoma
NCT01906814	PHASE3	UNKNOWN	Adjuvant Chemotherapy for High-risk Retinoblastoma After Enucleation
NCT01987596	PHASE3	TERMINATED	Study of Fixed vs. Flexible Filgrastim to Accelerate Bone Marrow Recovery After Chemotherapy in Children With Cancer
NCT02137928	PHASE3	UNKNOWN	Carboplatin Periocular Injection for Retinoblastoma
NCT04799002	PHASE3	RECRUITING	Topotecan and Melphalan for Retinoblastoma
NCT05080010	PHASE3	RECRUITING	Adjuvant Chemotherapy for High-risk Postenucleation Retinoblastoma
NCT00002515	PHASE2	COMPLETED	Combination Chemotherapy Followed by Bone Marrow Transplantation in Treating Patients With Rare Cancer
NCT00002675	PHASE2	COMPLETED	Chemotherapy in Treating Patients With Retinoblastoma
NCT00002794	PHASE2	COMPLETED	Carboplatin Plus Vincristine in Treating Children With Retinoblastoma
NCT00003173	PHASE2	COMPLETED	High-Dose Thiotepa Plus Peripheral Stem Cell Transplantation in Treating Patients With Refractory Solid Tumors
NCT00003273	PHASE2	WITHDRAWN	Chemotherapy Followed by Peripheral Stem Cell Transplantation in Treating Children With Newly Diagnosed Brain Tumor
NCT00004006	PHASE2	COMPLETED	Combination Chemotherapy, Radiation Therapy, and Bone Marrow Transplantation in Treating Patients With Retinoblastoma
NCT00006102	PHASE2	COMPLETED	Rebeccamycin Analogue in Treating Children With Solid Tumors or Non-Hodgkin’s Lymphoma
NCT00024258	PHASE2	COMPLETED	Arsenic Trioxide in Treating Patients With Advanced Neuroblastoma or Other Childhood Solid Tumors
NCT00110110	PHASE2	UNKNOWN	Combination Chemotherapy and Cyclosporine Followed by Focal Therapy for Bilateral Retinoblastoma
NCT00179920	PHASE2	COMPLETED	Chemotherapy Treatment for Children With Intraocular Germ-Line Retinoblastoma
NCT00432445	PHASE2	TERMINATED	Proton Beam Radiation Therapy for Intraocular and Periocular Retinoblastoma
NCT00445965	PHASE2	COMPLETED	Iodine I 131 Monoclonal Antibody 3F8 in Treating Patients With Central Nervous System Cancer or Leptomeningeal Cancer
NCT00831844	PHASE2	COMPLETED	Cixutumumab in Treating Patients With Relapsed or Refractory Solid Tumors
NCT01151748	PHASE2	WITHDRAWN	Intra-arterial Chemotherapy for Advanced Intraocular Retinoblastoma
NCT01293539	PHASE2	TERMINATED	Intra-arterial Chemotherapy for the Treatment of Intraocular Retinoblastoma
NCT01393769	PHASE2	TERMINATED	Intra-arterial Chemotherapy With Melphalan for the Treatment of Retinoblastoma (RTB) in Advanced Intraocular Stage
NCT01783535	PHASE2	ACTIVE_NOT_RECRUITING	Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma
NCT01857752	PHASE2	TERMINATED	Phase II Study Temozolomide for Retinoblastoma Metastatic to the Central Nervous System for Patients From Guatemala
NCT01899066	PHASE2	UNKNOWN	Efficacy Study of Lucentis in the Treatment of Retinoblastoma
NCT02866136	PHASE2	ACTIVE_NOT_RECRUITING	Conservative Treatments of Retinoblastoma
NCT02870907	PHASE2	ACTIVE_NOT_RECRUITING	Adjuvant Treatment in Extensive Unilateral Retinoblastoma Primary Enucleated (RB SFCE 2009)
NCT04455139	PHASE2	TERMINATED	A Prospective International Multicenter Clinical Trial for Eyes With Relapsed Retinoblastoma
NCT04990271	PHASE2	UNKNOWN	A Clinical Study on the Efficacy and Safety of VEC Intravenous Chemotherapy Combined With Conbercept Intravitreal Injection in the Treatment of Retinoblastoma
NCT05504291	PHASE2	RECRUITING	A Study to Give Treatment Inside the Eye to Treat Retinoblastoma
NCT06679634	PHASE2	RECRUITING	Retinoblastoma Phase II Expanded Access Clinical Trial
NCT00003022	PHASE1	COMPLETED	Monoclonal Antibody Therapy in Treating Patients With Leptomeningeal Cancer
NCT00003926	PHASE1	TERMINATED	Amifostine to Protect From Side Effects of PSCT in Treating Patients With Solid Tumors
NCT00006246	PHASE1	COMPLETED	Busulfan in Treating Children and Adolescents With Refractory CNS Cancer
NCT00012181	PHASE1	COMPLETED	Flavopiridol in Treating Children With Relapsed or Refractory Solid Tumors or Lymphomas
NCT00053118	PHASE1	COMPLETED	Chemotherapy and Stem Cell Transplantation in Treating Children With Central Nervous System Cancer
NCT00460876	PHASE1	COMPLETED	Phase I Trial of Periocular Topotecan in Retinoblastoma