TYROBP

Summary

TYROBP (transmembrane immune signaling adaptor TYROBP, HGNC:12449) is a protein-coding gene on chromosome 19q13.12, encoding TYRO protein tyrosine kinase-binding protein (O43914). Adapter protein which non-covalently associates with activating receptors found on the surface of a variety of immune cells to mediate signaling and cell activation following ligand binding by the receptors.

This gene encodes a transmembrane signaling polypeptide which contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. The encoded protein may associate with the killer-cell inhibitory receptor (KIR) family of membrane glycoproteins and may act as an activating signal transduction element. This protein may bind zeta-chain (TCR) associated protein kinase 70kDa (ZAP-70) and spleen tyrosine kinase (SYK) and play a role in signal transduction, bone modeling, brain myelination, and inflammation. Mutations within this gene have been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as Nasu-Hakola disease. Its putative receptor, triggering receptor expressed on myeloid cells 2 (TREM2), also causes PLOSL. Multiple alternative transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 7305 — RefSeq curated summary.

At a glance

• Gene–disease (curated): polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 122 total — 4 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 55
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_003332

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12449
Approved symbol	TYROBP
Name	transmembrane immune signaling adaptor TYROBP
Location	19q13.12
Locus type	gene with protein product
Status	Approved
Aliases	DAP12, PLO-SL, KARAP
Ensembl gene	ENSG00000011600
Ensembl biotype	protein_coding
OMIM	604142
Entrez	7305

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000262629, ENST00000424586, ENST00000544690, ENST00000585626, ENST00000585901, ENST00000586946, ENST00000587837, ENST00000588439, ENST00000589517, ENST00000895009, ENST00000956527, ENST00000956528, ENST00000956529, ENST00000956530

RefSeq mRNA: 4 — MANE Select: NM_003332 NM_001173514, NM_001173515, NM_003332, NM_198125

CCDS: CCDS12482, CCDS46058, CCDS54255, CCDS59378

Canonical transcript exons

ENST00000262629 — 5 exons

Exon	Start	End
ENSE00003461710	35904403	35904634
ENSE00003523162	35907730	35907762
ENSE00003552202	35907446	35907580
ENSE00003600798	35907218	35907264
ENSE00003621149	35908168	35908295

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 99.84.

FANTOM5 (CAGE): breadth broad, TPM avg 376.2885 / max 10354.5618, expressed in 575 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180607	376.2885	575

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.84	gold quality
mononuclear cell	CL:0000842	99.82	gold quality
leukocyte	CL:0000738	99.81	gold quality
granulocyte	CL:0000094	99.75	gold quality
blood	UBERON:0000178	99.69	gold quality
spleen	UBERON:0002106	99.34	gold quality
right lung	UBERON:0002167	99.32	gold quality
bone marrow	UBERON:0002371	99.27	gold quality
periodontal ligament	UBERON:0008266	98.96	gold quality
upper lobe of left lung	UBERON:0008952	98.90	gold quality
bone marrow cell	CL:0002092	98.77	gold quality
upper lobe of lung	UBERON:0008948	98.70	gold quality
gall bladder	UBERON:0002110	98.44	gold quality
right coronary artery	UBERON:0001625	98.36	gold quality
trabecular bone tissue	UBERON:0002483	98.32	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.38	gold quality
descending thoracic aorta	UBERON:0002345	97.30	gold quality
omental fat pad	UBERON:0010414	97.27	gold quality
vermiform appendix	UBERON:0001154	97.25	gold quality
peritoneum	UBERON:0002358	97.24	gold quality
middle frontal gyrus	UBERON:0002702	97.22	gold quality
layer of synovial tissue	UBERON:0007616	97.04	gold quality
synovial joint	UBERON:0002217	97.03	gold quality
lower lobe of lung	UBERON:0008949	96.95	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.87	gold quality
lymph node	UBERON:0000029	96.80	gold quality
right adrenal gland cortex	UBERON:0035827	96.79	gold quality
spinal cord	UBERON:0002240	96.76	gold quality
left adrenal gland cortex	UBERON:0035825	96.46	gold quality
left coronary artery	UBERON:0001626	96.44	gold quality

Single-cell (SCXA)

Detected in 71 experiment(s), a significant marker in 68.

Experiment	Marker?	Max mean expression
E-HCAD-15	yes	5426.36
E-HCAD-10	yes	5045.01
E-CURD-112	yes	5027.37
E-MTAB-8207	yes	4832.56
E-MTAB-6653	yes	4825.46
E-HCAD-4	yes	4556.96
E-HCAD-1	yes	4548.34
E-MTAB-6308	yes	4445.33
E-MTAB-7407	yes	4403.82
E-MTAB-6701	yes	4307.95
E-MTAB-10553	yes	4226.83
E-CURD-120	yes	4105.62
E-GEOD-139324	yes	4031.42
E-MTAB-10042	yes	3968.16
E-CURD-126	yes	3931.78

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CD68	Activation
CD86	Activation

Upstream regulators (CollecTRI, top): EGR3, SPI1

miRNA regulators (miRDB)

13 targeting TYROBP, 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-9718	99.94	68.91	918
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-628-5P	98.36	67.74	844
HSA-MIR-4518	98.12	66.82	1030
HSA-MIR-6842-3P	98.07	66.33	1325
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-1266-5P	97.71	66.92	1052
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-5192	96.89	63.35	879
HSA-MIR-134-3P	96.83	66.22	1001
HSA-MIR-571	95.38	66.54	671

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Mutations in two genes encoding different subunits of a receptor signaling complex (TYROBP and TREM2) result in an identical disease phenotype (PMID:12080485)
• Myeloid abnormalities seen in KARAP/DAP12-transgenic mice indicate that KARAP/DAP12-driven signals are involved in inflammation & constitute an essential target to control resolution of inflammatory disorders based on monocytes/macrophages & neutrophils. (PMID:12207350)
• DAP12 has a role in signal transduction, bone modeling, and brain myelination [review] (PMID:12569153)
• CD158j in T cells functions as a costimulatory molecule through the JNK pathway independent of KARAP/DAP12 and DAP10. (PMID:12591902)
• These results indicate an important role for DAP12-TREM2 signaling complex in the differentiation and function of osteoclasts. (PMID:12925681)
• DAP12 association with natural cytotoxicity receptor NKp44 is required for activating properties and surface expression of NKp44 in natural killer (NK) cells. (PMID:14707061)
• In clones that lack expression of KARAP/DAP12, stimulation of killer Ig-receptor KIR2DS2 does not induce cytotoxicity, whereas expression of KARAP/DAP12 is sufficient to convert a costimulatory KIR receptor into a stimulatory molecule. (PMID:15356118)
• Splenic mature dendritic cells from transgenic mice with DAP12 overexpression are characterized by an impaired tolerogenic potential (PMID:16206234)
• requirement by activated and expanded CD8+ T cells for DAP12 for direct killing (PMID:16339517)
• Nasu-Hakola disease due to a DAP12 mutation 4. (PMID:16505336)
• This review discusses the dual functionality of DAP12 and presents evidence that DAP12 can suppress as well as activate natural killer (NK) cells. (PMID:17100880)
• This is the first case of Nasu-Hakola disease caused by compound heterozygosity for loss-of-function mutations in DAP12. (PMID:17125796)
• KIR3DS1 associates with the ITAM-bearing adaptor, DAP12 (PMID:17202323)
• activation signals delivered via DAP12 can be counterbalanced by the adaptor NTAL (PMID:17277102)
• Transcript analysis of DCs of PLOSL patients show that DAP12 deficient cells differentiated into DCs and responded to pathogenic stimuli. However, the DCs showed morphological differences due to defects in the actin filaments. (PMID:17530208)
• the DAP12-TREM2 complex unlikely has a role in genetic susceptibility of multiple sclerosis (PMID:19019460)
• Downstream targets of DAP10 and DAP12 are constitutively activated in large granular lymphocyte leukemia cells, and expression of dominant-negative DAP10 and DAP12 dramatically reduces their lytic capacity. (PMID:19075187)
• loss of function mutation results in recessive genetic disorder, Nasu-Hakola disease (bone development abnormalities and dementia at adolescence) (PMID:19120482)
• describe the generation and the characterization of an anti-DAP12 monoclonal antibody. Using this novel reagent, we show that DAP12 expression is restricted to innate immune cells in basal condition (PMID:19606219)
• DAP12-associating lectin (MDL)-1 receptor is a key regulator of synovial injury and bone erosion in autoimmune joint inflammation. (PMID:20212065)
• These findings indicate that DAP12, possibly through association with TREM2, contributes to alveolar macrophage chemotaxis and recruitment to the lung and may mediate macrophage accumulation in lung diseases such as emphysema. (PMID:20421649)
• A transgenic mouse model demonstrates that induction of tolerance in Ly49H-positive natural killer (NK) cells by chronic exposure to virus-encoded ligand m157 requires signaling through the Ly49H adaptor protein DAP12, not the DAP10 adaptor protein. (PMID:21263069)
• DAP12 gene levels were not increased in the monocytes of schizophrenic, bioplar or major depressive disorder patients. (PMID:21421043)
• Data suggest that OSCAR is a collagen receptor that binds to specific collagen motifs and costimulates osteoclastogenesis in DAP12-deficient humans and mice. (PMID:21841309)
• the putative periodontal pathogen P. gingivalis can positively regulate the expression of the TREM-1/DAP12 pathway in monocytic cells. (PMID:21967868)
• A molecular defect of DAP12 in human monocytes deregulates the gene network pivotal for maintenance of myeloid cell function in Nasu-Hakola disease. (PMID:22080356)
• dynamics and dimerization of the TM helix of DAP12 in the membrane bilayer (PMID:23561520)
• DAP12 has a role in trafficking newly synthesized KIR to the cell surface. It interacts with an immature KIR2DS isoform likely initiating in the ER. DAP12also impacts KIR2DS surface stability. (PMID:23715743)
• Macrophage traits in BRC cells facilitate the metastatic process and DAP12 expression might promote metastatic homing to bone and liver tissues. (PMID:23810293)
• Its mutation is a known genetic cause of Nasu-Hakola disease. (PMID:24612676)
• Data indicate that NKG2 receptor NKG2E was capable of associating with CD94 and DAP12 but that the complex was retained intracellularly at the endoplasmic reticulum. (PMID:24935923)
• This study reveled that TYROBP having a central role in the bipolar disease and schizophrenia manifestation. (PMID:25487697)
• isolated PMNs have an increased proportion of both TREM1 and DAP12 compared to normal healthy control (PMID:25642940)
• T cells modified to express a KIR-CAR and DAP12 exhibit superior antitumor activity compared with standard first- and second-generation CD3zeta-based CARs in a xenograft model of mesothelioma highly resistant to immunotherapy. (PMID:25941351)
• results support a role of DAP12 in stabilizing TREM2-CTF, thereby protecting against excessive pro-inflammatory responses. (PMID:25957402)
• The different expression of DAP12 compared to TREM2 represents the first description of such variable expressivity in Nasu-Hakola disease (NHD) microglia. (PMID:26001891)
• Impaired signaling by the TREM2-DAP12 pathway leads to altered immune responses in phagocytosis, cytokine production, and microglial proliferation and survival, thus contributing to disease pathogenesis. Review. (PMID:26337043)
• the microglial membrane adaptor protein DAP12 was required for both nerve injury- and intrathecal CSF1-induced upregulation of pain-related microglial genes and the ensuing pain, but not for microglial proliferation (PMID:26642091)
• TYROBP/CSTA gene interaction might play pivotal roles in the occurrence and development of Postmenopausal Osteoporosis (PMID:26676054)
• TYROBP influences a batch of genes that are related to Alzheimer’s disease; ZNF329 and RB1 significantly regulate those ‘mesenchymal’ gene expression signature genes for brain tumors. By merely leveraging gene expression data, Context Based Dependency Network (CBDN) can efficiently infer the existence of gene-gene interactions as well as their regulatory directions. (PMID:27556418)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tyrobp	ENSDARG00000094894
mus_musculus	Tyrobp	ENSMUSG00000030579
rattus_norvegicus	Tyrobp	ENSRNOG00000020845

Protein

Protein identifiers

TYRO protein tyrosine kinase-binding protein — O43914 (reviewed: O43914)

Alternative names: DNAX-activation protein 12, Killer-activating receptor-associated protein

All UniProt accessions (4): O43914, K7EKK0, K7ES93, X6RGC9

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein which non-covalently associates with activating receptors found on the surface of a variety of immune cells to mediate signaling and cell activation following ligand binding by the receptors. TYROBP is tyrosine-phosphorylated in the ITAM domain following ligand binding by the associated receptors which leads to activation of additional tyrosine kinases and subsequent cell activation. Also has an inhibitory role in some cells. Non-covalently associates with activating receptors of the CD300 family to mediate cell activation. Also mediates cell activation through association with activating receptors of the CD200R family. Required for neutrophil activation mediated by integrin. Required for the activation of myeloid cells mediated by the CLEC5A/MDL1 receptor. Associates with natural killer (NK) cell receptors such as KIR2DS2 and the KLRD1/KLRC2 heterodimer to mediate NK cell activation. Also enhances trafficking and cell surface expression of NK cell receptors KIR2DS1, KIR2DS2 and KIR2DS4 and ensures their stability at the cell surface. Associates with SIRPB1 to mediate activation of myeloid cells such as monocytes and dendritic cells. Associates with TREM1 to mediate activation of neutrophils and monocytes. Associates with TREM2 on monocyte-derived dendritic cells to mediate up-regulation of chemokine receptor CCR7 and dendritic cell maturation and survival. Association with TREM2 mediates cytokine-induced formation of multinucleated giant cells which are formed by the fusion of macrophages. Stabilizes the TREM2 C-terminal fragment (TREM2-CTF) produced by TREM2 ectodomain shedding which suppresses the release of pro-inflammatory cytokines. In microglia, required with TREM2 for phagocytosis of apoptotic neurons. Required with ITGAM/CD11B in microglia to control production of microglial superoxide ions which promote the neuronal apoptosis that occurs during brain development. Promotes pro-inflammatory responses in microglia following nerve injury which accelerates degeneration of injured neurons. Positively regulates the expression of the IRAK3/IRAK-M kinase and IL10 production by liver dendritic cells and inhibits their T cell allostimulatory ability. Negatively regulates B cell proliferation. Required for CSF1-mediated osteoclast cytoskeletal organization. Positively regulates multinucleation during osteoclast development.

Subunit / interactions. Homodimer; disulfide-linked. Homotrimer; disulfide-linked. Homotetramer; disulfide-linked. Homotrimers and homotetramers form when low levels of partner receptors are available and are competitive with assembly with interacting receptors. They may represent alternative oligomerization states or may be intermediates in the receptor assembly process. Binding of a metal cation aids in homooligomerization through coordination of the metal ion by the subunits of the oligomer. Interacts with TREM1. Interacts with TREM2. Interacts with SIRPB1. Interacts with CLECSF5. Interacts with SIGLEC14. Interacts with CD300LB and CD300E. Interacts with CD300C2. Interacts (via ITAM domain) with SYK (via SH2 domains); activates SYK mediating neutrophil and macrophage integrin-mediated activation. Interacts with KLRC2, KIR2DS3 and KIR2DS5. Interacts with CD300H. Interacts with KIR2DS1. Interacts with KLRD1. Interacts with SIGLEC1.

Subcellular location. Cell membrane.

Tissue specificity. Expressed at low levels in the early development of the hematopoietic system and in the promonocytic stage and at high levels in mature monocytes. Expressed in hematological cells and tissues such as peripheral blood leukocytes and spleen. Also found in bone marrow, lymph nodes, placenta, lung and liver. Expressed at lower levels in different parts of the brain especially in the basal ganglia and corpus callosum.

Post-translational modifications. Following ligand binding by associated receptors, tyrosine phosphorylated in the ITAM domain which leads to activation of additional tyrosine kinases and subsequent cell activation.

Disease relevance. Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 (PLOSL1) [MIM:221770] A recessively inherited disease characterized by presenile dementia along with large-scale destruction of cancellous bones. Initial symptoms, starting in the twenties, are pain and swelling resulting from cysts in the wrists and ankles. Extremity bone fractures could occur with minor trauma. At around 30 years of age, patients gradually develop neuropsychiatric symptoms, including epileptic seizures, agnosia, apraxia, speech disorder, memory disturbance, euphoria, and loss of social inhibitions. The disorder usually leads to death in the fifth decade of life. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TYROBP family.

Isoforms (3)

UniProt ID	Names	Canonical?
O43914-1	1, KARAP-a	yes
O43914-2	2, KARAP-b
O43914-3	3

RefSeq proteins (4): NP_001166985, NP_001166986, NP_003323, NP_937758 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026200	Tyrobp	Family

UniProt features (32 total): sequence variant 9, mutagenesis site 7, modified residue 2, splice variant 2, topological domain 2, signal peptide 1, chain 1, disulfide bond 1, transmembrane region 1, helix 1, domain 1, region of interest 1, compositionally biased region 1, binding site 1, site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4WOL	X-RAY DIFFRACTION	1.77
4WO1	X-RAY DIFFRACTION	2.14
7Q5W	X-RAY DIFFRACTION	2.2
2L34	SOLUTION NMR
2L35	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43914-F1	64.10	0.14

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): 54 (important for interaction with transmembrane receptors)

Ligand- & substrate-binding residues (1): 50

Post-translational modifications (2): 91, 102

Disulfide bonds (1): 35

Mutagenesis-validated functional residues (7):

Position	Phenotype
41	does not significantly alter the formation of homotrimers or homotetramers; when associated with l-45 and l-49.
45	does not significantly alter the formation of homotrimers or homotetramers; when associated with l-41 and l-49.
49	does not significantly alter the formation of homotrimers or homotetramers; when associated with l-41 and l-45.
50	reduced cell surface expression of kir2ds1. severely impairs formation of homotrimers and homotetramers. abolishes inter
50	severely impairs formation of homotrimers and homotetramers.
50	reduces formation of homotrimers and homotetramers.
54	reduced interaction with klrc2 and kir2ds3. reduces homotrimer formation and increases homotetramer formation.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-2172127	DAP12 interactions
R-HSA-2424491	DAP12 signaling
R-HSA-391160	Signal regulatory protein family interactions
R-HSA-416700	Other semaphorin interactions
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 593 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, MCLACHLAN_DENTAL_CARIES_UP, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, GOBP_B_CELL_ACTIVATION, GOCC_SECRETORY_GRANULE, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE

GO Biological Process (47): stimulatory killer cell immunoglobulin-like receptor signaling pathway (GO:0002222), stimulatory C-type lectin receptor signaling pathway (GO:0002223), natural killer cell mediated immunity (GO:0002228), myeloid leukocyte activation (GO:0002274), microglial cell activation involved in immune response (GO:0002282), neutrophil activation involved in immune response (GO:0002283), T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell (GO:0002291), cellular defense response (GO:0006968), signal transduction (GO:0007165), integrin-mediated signaling pathway (GO:0007229), positive regulation of gene expression (GO:0010628), actin cytoskeleton organization (GO:0030036), osteoclast differentiation (GO:0030316), negative regulation of B cell proliferation (GO:0030889), forebrain development (GO:0030900), negative regulation of type I interferon production (GO:0032480), negative regulation of interleukin-10 production (GO:0032693), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), positive regulation of natural killer cell activation (GO:0032816), negative regulation of transforming growth factor beta1 production (GO:0032911), positive regulation of superoxide anion generation (GO:0032930), positive regulation of macrophage fusion (GO:0034241), intracellular signal transduction (GO:0035556), apoptotic cell clearance (GO:0043277), response to axon injury (GO:0048678), protein stabilization (GO:0050821), semaphorin-plexin signaling pathway (GO:0071526), amyloid-beta clearance (GO:0097242), negative regulation of long-term synaptic potentiation (GO:1900272), positive regulation of receptor localization to synapse (GO:1902685), positive regulation of microglial cell mediated cytotoxicity (GO:1904151), cellular response to amyloid-beta (GO:1904646), positive regulation of protein localization to cell surface (GO:2000010), positive regulation of osteoclast development (GO:2001206), negative regulation of cytokine production (GO:0001818), immune effector process (GO:0002252), macrophage activation involved in immune response (GO:0002281), immune system process (GO:0002376)

GO Molecular Function (7): signaling receptor binding (GO:0005102), protein-macromolecule adaptor activity (GO:0030674), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), molecular adaptor activity (GO:0060090), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), secretory granule membrane (GO:0030667)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Innate Immune System	2
Adaptive Immune System	1
DAP12 interactions	1
Cell-Cell communication	1
Semaphorin interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
innate immune response activating cell surface receptor signaling pathway	2
immune response	2
negative regulation of cytokine production	2
binding	2
cellular anatomical structure	2
cellular response to lectin	1
lymphocyte mediated immunity	1
innate immune response	1
leukocyte activation	1
microglial cell activation	1
macrophage activation involved in immune response	1
myeloid cell activation involved in immune response	1
neutrophil activation	1
T cell activation involved in immune response	1
defense response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
cytoskeleton organization	1
actin filament-based process	1
myeloid leukocyte differentiation	1
regulation of B cell proliferation	1
B cell proliferation	1
negative regulation of lymphocyte proliferation	1
negative regulation of B cell activation	1
brain development	1
anatomical structure development	1
regulation of type I interferon production	1
type I interferon production	1
interleukin-10 production	1
regulation of interleukin-10 production	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1

Protein interactions and networks

STRING

2604 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TYROBP	TREM2	Q9NZC2	999
TYROBP	NCR2	O95944	997
TYROBP	SYK	P43405	997
TYROBP	KLRK1	P26718	996
TYROBP	TREM1	Q9NP99	996
TYROBP	KLRC2	P26717	994
TYROBP	ZAP70	P43403	994
TYROBP	SIGLEC14	Q08ET2	991
TYROBP	KLRD1	Q13241	991
TYROBP	SIRPB1	O00241	990
TYROBP	CLEC5A	Q9NY25	990
TYROBP	HCST	Q9UBK5	978
TYROBP	OSCAR	Q8IYS5	978
TYROBP	NCR1	O76036	973
TYROBP	FCER1G	P30273	964

IntAct

39 interactions, top by confidence:

A	B	Type	Score
TREM2	TYROBP	psi-mi:“MI:0915”(physical association)	0.670
TREM2	TYROBP	psi-mi:“MI:0403”(colocalization)	0.670
NCR2	TYROBP	psi-mi:“MI:0915”(physical association)	0.590
KIR2DS5	TYROBP	psi-mi:“MI:0915”(physical association)	0.590
TYROBP	SLC35B4	psi-mi:“MI:0915”(physical association)	0.560
TYROBP	TMEM86A	psi-mi:“MI:0915”(physical association)	0.560
TYROBP	TYROBP	psi-mi:“MI:0407”(direct interaction)	0.560
TYROBP	SIRPB1	psi-mi:“MI:0915”(physical association)	0.520
SIRPB1	TYROBP	psi-mi:“MI:0915”(physical association)	0.520
TYROBP		psi-mi:“MI:0407”(direct interaction)	0.440
TREM1	TYROBP	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC14	TYROBP	psi-mi:“MI:0915”(physical association)	0.400
TYROBP	SYK	psi-mi:“MI:0915”(physical association)	0.400
TYROBP	CD300C	psi-mi:“MI:0915”(physical association)	0.400
TYROBP	CD300LD	psi-mi:“MI:0915”(physical association)	0.400
KLRC2	TYROBP	psi-mi:“MI:0915”(physical association)	0.400
TYROBP	KIR2DS3	psi-mi:“MI:0915”(physical association)	0.400
CD300H	TYROBP	psi-mi:“MI:0914”(association)	0.350
SLC15A4	ESYT2	psi-mi:“MI:0914”(association)	0.350
TYROBP	MTHFR	psi-mi:“MI:0914”(association)	0.350
TYROBP	KCNN4	psi-mi:“MI:0914”(association)	0.350

BioGRID (80): TMEM86A (Two-hybrid), SLC35B4 (Two-hybrid), TYROBP (Affinity Capture-Western), SIRPB1 (Affinity Capture-Western), TYROBP (Affinity Capture-Western), EXTL2 (Affinity Capture-MS), NOP9 (Affinity Capture-MS), FAM134C (Affinity Capture-MS), TMX4 (Affinity Capture-MS), GPIHBP1 (Affinity Capture-MS), GBF1 (Affinity Capture-MS), SLC35B2 (Affinity Capture-MS), DNM3 (Affinity Capture-MS), DNM2 (Affinity Capture-MS), MTHFR (Affinity Capture-MS)

ESM2 similar proteins: A4F4L0, O00453, O14669, O43914, O54885, P04234, P04235, P07766, P0CAN6, P18438, P19377, P20963, P24161, P29328, P29329, P59646, Q13113, Q28072, Q28073, Q2KIP5, Q3TYX2, Q5R1Q1, Q5RA41, Q63113, Q64159, Q6AYD4, Q6ITQ4, Q6X9T7, Q764N2, Q8K1T1, Q8MII8, Q8N386, Q8NET5, Q8R182, Q8WNQ8, Q923S2, Q925F2, Q95J79, Q95LI5, Q95LI8

Diamond homologs: A4F4L0, O43914, O54885, Q6X9T7, Q8WNQ8, Q95J79, Q9TU45, P04234, P04235, P09693, P11942, P18438, P18439, P19377, Q28072, Q28073, Q28074, Q5PXD3, Q64159, Q764N2, Q95LI7, Q95LI8, Q98910

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CD300LB	“up-regulates activity”	TYROBP	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 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
DAP12 interactions	7	237.9×	2e-14
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	5	31.1×	1e-05
Innate Immune System	5	9.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	3
Uncertain significance	49
Likely benign	40
Benign	8

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1935007	NM_003332.4(TYROBP):c.82C>T (p.Gln28Ter)	Pathogenic
2424673	NC_000019.9:g.(?36398100)(36399130_?)del	Pathogenic
3660636	NM_003332.4(TYROBP):c.214C>T (p.Arg72Ter)	Pathogenic
5797	NM_003332.4(TYROBP):c.2T>C (p.Met1Thr)	Pathogenic
4849333	NM_003332.4(TYROBP):c.178del (p.Ala60fs)	Likely pathogenic
56394	NM_003332.4(TYROBP):c.116G>A (p.Ser39Asn)	Likely pathogenic
56397	NM_003332.4(TYROBP):c.262G>T (p.Glu88Ter)	Likely pathogenic

SpliceAI

687 predictions. Top by Δscore:

Variant	Effect	Δscore
19:35907281:T:C	acceptor_gain	1.0000
19:35907281:T:TC	acceptor_gain	1.0000
19:35907283:G:C	acceptor_gain	1.0000
19:35907288:G:C	acceptor_gain	1.0000
19:35907288:G:GC	acceptor_gain	1.0000
19:35908167:CCA:C	donor_gain	1.0000
19:35908173:A:AC	donor_gain	1.0000
19:35908173:ACAG:A	donor_gain	1.0000
19:35908174:C:CC	donor_gain	1.0000
19:35908174:CAG:C	donor_gain	1.0000
19:35908174:CAGC:C	donor_gain	1.0000
19:35907278:G:C	acceptor_gain	0.9900
19:35907278:G:GC	acceptor_gain	0.9900
19:35907283:G:GC	acceptor_gain	0.9900
19:35907291:C:CT	acceptor_gain	0.9900
19:35907444:AC:A	donor_gain	0.9900
19:35907445:CC:C	donor_gain	0.9900
19:35908161:AACT:A	donor_loss	0.9900
19:35908162:ACT:A	donor_loss	0.9900
19:35908163:CTC:C	donor_loss	0.9900
19:35908164:T:TC	donor_loss	0.9900
19:35908165:C:CG	donor_loss	0.9900
19:35908166:A:AC	donor_gain	0.9900
19:35908167:C:CC	donor_gain	0.9900
19:35908167:C:CG	donor_loss	0.9900
19:35904630:AGCTC:A	acceptor_gain	0.9800
19:35904632:CTC:C	acceptor_gain	0.9800
19:35904634:CCTAA:C	acceptor_loss	0.9800
19:35904635:C:CC	acceptor_gain	0.9800
19:35904899:T:TA	donor_gain	0.9800

AlphaMissense

704 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:35907530:C:G	G49R	0.997
19:35907530:C:T	G49R	0.997
19:35907505:A:T	I57N	0.995
19:35907502:G:T	A58D	0.994
19:35907514:G:C	T54R	0.993
19:35907514:G:T	T54K	0.993
19:35907529:C:T	G49E	0.993
19:35904630:A:T	L94H	0.990
19:35907223:A:G	Y91H	0.990
19:35907514:G:A	T54I	0.989
19:35907517:A:C	L53R	0.989
19:35907517:A:G	L53P	0.989
19:35907523:A:G	L51P	0.989
19:35907538:A:T	I46N	0.989
19:35907526:T:G	D50A	0.988
19:35907525:G:C	D50E	0.987
19:35907525:G:T	D50E	0.987
19:35907541:C:T	G45E	0.987
19:35904607:A:G	Y102H	0.985
19:35907526:T:C	D50G	0.985
19:35907527:C:G	D50H	0.985
19:35907535:A:T	V47E	0.985
19:35907542:C:G	G45R	0.985
19:35907542:C:T	G45R	0.985
19:35907491:A:C	Y62D	0.983
19:35904602:G:C	S103R	0.982
19:35904602:G:T	S103R	0.982
19:35904604:T:G	S103R	0.982
19:35907496:G:T	A60D	0.982
19:35904597:A:T	L105H	0.981

dbSNP variants (sampled 300 via entrez): RS1000373063 (19:35909859 G>A), RS1000845620 (19:35907199 G>C), RS1000904526 (19:35905898 A>G), RS1001378227 (19:35906177 GC>G), RS1001882725 (19:35906039 G>C,T), RS1002261404 (19:35905677 G>A,T), RS1002399693 (19:35905673 G>A,C), RS1002975680 (19:35908631 C>T), RS1003299336 (19:35909817 G>A), RS1003812695 (19:35906339 T>C), RS1004074567 (19:35906081 G>A), RS1004439964 (19:35905343 C>T), RS1004617798 (19:35910121 G>A), RS1004803489 (19:35906853 A>C,G), RS1005809781 (19:35905632 G>A)

Disease associations

OMIM: gene MIM:604142 | disease phenotypes: MIM:221770

GenCC curated gene-disease

Disease	Classification	Inheritance
polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1	Strong	Autosomal recessive
polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly	Supportive	Autosomal recessive

Mondo (4): polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 (MONDO:0020749), dementia (MONDO:0001627), parkinsonian disorder (MONDO:0021095), polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly (MONDO:0009092)

Orphanet (1): Nasu-Hakola disease (Orphanet:2770)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000238	Hydrocephalus
HP:0000657	Oculomotor apraxia
HP:0000708	Atypical behavior
HP:0000718	Aggressive behavior
HP:0000719	Inappropriate behavior
HP:0000726	Dementia
HP:0000727	Frontal lobe dementia
HP:0000734	Disinhibition
HP:0000737	Irritability
HP:0000751	Personality changes
HP:0000757	Lack of insight
HP:0001155	Abnormality of the hand
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001288	Gait disturbance
HP:0001336	Myoclonus
HP:0001376	Limitation of joint mobility
HP:0001760	Abnormal foot morphology
HP:0002059	Cerebral atrophy
HP:0002072	Chorea
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002120	Cerebral cortical atrophy
HP:0002127	Abnormal upper motor neuron morphology
HP:0002135	Basal ganglia calcification
HP:0002167	Abnormal speech pattern
HP:0002171	Gliosis
HP:0002186	Apraxia

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003704	Dementia	C10.228.140.380; F03.615.400
D020734	Parkinsonian Disorders	C10.228.140.079.862; C10.228.662.600

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tretinoin	increases expression	5
Calcitriol	decreases expression, increases expression	3
Benzo(a)pyrene	affects cotreatment, affects expression, affects methylation	2
Nickel	increases expression	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
fluoranthene	affects cotreatment, affects expression	1
sulforaphane	increases expression	1
sodium arsenite	affects expression	1
pyrrolidine dithiocarbamic acid	affects cotreatment, decreases expression, decreases reaction	1
1,2,5,6-dibenzanthracene	affects cotreatment, affects expression	1
bathocuproine sulfonate	affects cotreatment, decreases expression, decreases reaction	1
dibenzo(a,l)pyrene	affects cotreatment, affects expression	1
tamibarotene	increases expression	1
entinostat	increases expression	1
nutlin 3	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cisplatin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Methotrexate	decreases expression	1
Tetradecanoylphorbol Acetate	affects cotreatment, decreases expression, decreases reaction	1
Valproic Acid	decreases expression, increases methylation	1
Ionomycin	affects cotreatment, decreases expression, decreases reaction	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

7 cell lines: 3 transformed cell line, 2 cancer cell line, 2 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7TG	Abcam THP-1 TYROBP KO	Cancer cell line	Male
CVCL_E6RQ	Genomeditech CHO-K1 H_SIGLEC15+TYROBP	Spontaneously immortalized cell line	Female
CVCL_E6SB	Genomeditech CHO-K1 H_TREM1+TYROBP	Spontaneously immortalized cell line	Female
CVCL_E6UU	Genomeditech HEK-293 H_SIGLEC15+TYROBP	Transformed cell line	Female
CVCL_E6V9	Genomeditech HEK-293 H_TREM1+TYROBP	Transformed cell line	Female
CVCL_E6VA	Genomeditech HEK-293 H_TREM2+TYROBP	Transformed cell line	Female
CVCL_E6WL	Genomeditech MC-38 H_SIGLEC15+TYROBP	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00043849	PHASE4	COMPLETED	Treatment of Agitation/Psychosis in Dementia/Parkinsonism (TAP/DAP)
NCT00127114	PHASE4	WITHDRAWN	Amantadine for the Treatment of Behavioral Disturbance in Frontotemporal Dementia (FTD)
NCT00164970	PHASE4	COMPLETED	Can Oral Vitamin B12 and Folate Supplementation Preserve Cognitive Function of Patients With Early Dementia?
NCT00177671	PHASE4	COMPLETED	Antidepressant Medication Plus Donepezil for Treating Late-life Depression
NCT00208819	PHASE4	COMPLETED	A Comparison of Two Standard Therapies in the Management of Dementia With Agitation
NCT00245206	PHASE4	COMPLETED	Side Effects of Newer Antipsychotics in Older Adults
NCT00254033	PHASE4	COMPLETED	Apathy Associated With Alzheimer’s Disease
NCT00371059	PHASE4	COMPLETED	Memantine for Agitation in Dementia
NCT00375557	PHASE4	WITHDRAWN	Safety and Efficacy of Divalproex and Quetiapine in Elderly Alzheimer’s Dementia Patients
NCT00385684	PHASE4	COMPLETED	Low-Dose Opiate Therapy for Discomfort in Dementia (L-DOT)
NCT00433121	PHASE4	COMPLETED	Discontinuation of Antipsychotics and Antidepressants Among Patients With BPSD
NCT00450047	PHASE4	COMPLETED	Study on the Efficacy of Speed-Feedback Therapy for Elderly People With Dementia
NCT00495820	PHASE4	COMPLETED	Methylphenidate for Apathy in Alzheimer’s Dementia: A Controlled Study
NCT00594269	PHASE4	COMPLETED	Dementia Antipsychotics And Antidepressants Discontinuation Study
NCT00626613	PHASE4	UNKNOWN	The Relationship Between Risperdal Treatment and Quality of Life in Patients With Alzheimer’s Disease and Behavioural and Psychological Symptoms of Dementia (BPSD)
NCT00768261	PHASE4	COMPLETED	Corticolimbic Degeneration and Treatment of Dementia
NCT00792662	PHASE4	WITHDRAWN	Improving Function, Quality of Life, Glycemia in Diabetics With Dementia
NCT00814658	PHASE4	COMPLETED	The Use of Galantamine (Reminyl ER) in Patients With MIXed Dementia: Effects on Cognition and Quality of Life
NCT00914095	PHASE4	COMPLETED	Study of Methylphenidate to Treat Gait Disorders And Attention Deficit In Parkinson’s Disease (PARKGAIT-II)
NCT01012830	PHASE4	UNKNOWN	Huperzine-A to Help With Mental Problems and the Inability to Care for Onself in Patients With Schizophrenia
NCT01109836	PHASE4	COMPLETED	Austrian Polyintervention Study to Prevent Cognitive Decline After Ischemic Stroke
NCT01340950	PHASE4	COMPLETED	Clinical Trial of Brain-Penetrating HIV Drugs to Prevent Cognitive Impairment in China
NCT01453127	PHASE4	ENROLLING_BY_INVITATION	DaTSCAN Imaging in Aging and Neurodegenerative Disease
NCT01799941	PHASE4	COMPLETED	Safety, Tolerability and Effectiveness of Nuedexta in the Treatment of Pseudobulbar Affect (PBA)
NCT01825577	PHASE4	TERMINATED	Exploring the Use of Transdermal Methylphenidate to Reduce Fall Risk in Patients With Dementia.
NCT01849042	PHASE4	UNKNOWN	Effect of Memantine Oral Pump on Language in Patients With Probable Alzheimer’s Disease
NCT02267057	PHASE4	COMPLETED	Efficacy of Pain Treatment on Depression in Patients With Dementia
NCT02782429	PHASE4	UNKNOWN	The Role of Ketamine in Preventing Cognitive Dysfunctions in Postoperative Period of Cardiac Surgery
NCT03061006	PHASE4	COMPLETED	Impact of Anticoagulation Therapy on the Cognitive Decline and Dementia in Patients With Non-Valvular Atrial Fibrillation
NCT03066518	PHASE4	COMPLETED	Effect of Melatonin on Sleep Quality in Patients Dementia
NCT03221751	PHASE4	TERMINATED	Prazosin and Cerebrospinal Fluid (CSF) Biomarkers in Mild Traumatic Brain Injury (mTBI)
NCT03817931	PHASE4	COMPLETED	Higher Neural Changes Following Anticholinergic, Beta 3 Agonist, or Placebo in Patients With Overactive Bladder
NCT04117178	PHASE4	COMPLETED	Monitoring Anti-Dementia Drugs by Serum Levels
NCT04262206	PHASE4	RECRUITING	Pragmatic Evaluation of Events And Benefits of Lipid-lowering in Older Adults
NCT04294654	PHASE4	COMPLETED	Vortioxetine in Patients With Depression and Early Dementia
NCT05514106	PHASE4	ENROLLING_BY_INVITATION	MIBG in Aging and Neurologic Disorders
NCT05531591	PHASE4	COMPLETED	RCT of Brain Longitudinal Biomarker Study (OPT-Neuro RCT)
NCT05855863	PHASE4	NOT_YET_RECRUITING	Clinical Study of GKT in Diabetes Related Dementia
NCT06093126	PHASE4	RECRUITING	Lemborexant for Insomnia in a Patient With Dementia: An N-of-1 Trial
NCT06662526	PHASE4	NOT_YET_RECRUITING	Lithium for Prevention of Cognitive Declining in Mood Illnesses