LITAF

Summary

LITAF (lipopolysaccharide induced TNF factor, HGNC:16841) is a protein-coding gene on chromosome 16p13.13, encoding Lipopolysaccharide-induced tumor necrosis factor-alpha factor (Q99732). Plays a role in endosomal protein trafficking and in targeting proteins for lysosomal degradation.

Lipopolysaccharide is a potent stimulator of monocytes and macrophages, causing secretion of tumor necrosis factor-alpha (TNF-alpha) and other inflammatory mediators. This gene encodes lipopolysaccharide-induced TNF-alpha factor, which is a DNA-binding protein and can mediate the TNF-alpha expression by direct binding to the promoter region of the TNF-alpha gene. The transcription of this gene is induced by tumor suppressor p53 and has been implicated in the p53-induced apoptotic pathway. Mutations in this gene cause Charcot-Marie-Tooth disease type 1C (CMT1C) and may be involved in the carcinogenesis of extramammary Paget’s disease (EMPD). Multiple alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 9516 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease type 1C (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 99
• Clinical variants (ClinVar): 319 total — 5 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Transcription factor: yes — 28 downstream targets (CollecTRI)
• MANE Select transcript: NM_001136472

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16841
Approved symbol	LITAF
Name	lipopolysaccharide induced TNF factor
Location	16p13.13
Locus type	gene with protein product
Status	Approved
Aliases	PIG7, SIMPLE, FLJ38636, TP53I7
Ensembl gene	ENSG00000189067
Ensembl biotype	protein_coding
OMIM	603795
Entrez	9516

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 41 protein_coding, 2 nonsense_mediated_decay

ENST00000339430, ENST00000413364, ENST00000570798, ENST00000570904, ENST00000571277, ENST00000571459, ENST00000571627, ENST00000571688, ENST00000571976, ENST00000572255, ENST00000573332, ENST00000574701, ENST00000574703, ENST00000574763, ENST00000574848, ENST00000575426, ENST00000576036, ENST00000576334, ENST00000622633, ENST00000888115, ENST00000888116, ENST00000888117, ENST00000888118, ENST00000888119, ENST00000888120, ENST00000888121, ENST00000888122, ENST00000888123, ENST00000888124, ENST00000928730, ENST00000928731, ENST00000928732, ENST00000928733, ENST00000928734, ENST00000928735, ENST00000928736, ENST00000928737, ENST00000928738, ENST00000941085, ENST00000941086, ENST00000941087, ENST00000941088, ENST00000941089

RefSeq mRNA: 3 — MANE Select: NM_001136472 NM_001136472, NM_001136473, NM_004862

CCDS: CCDS32386, CCDS45411

Canonical transcript exons

ENST00000622633 — 4 exons

Exon	Start	End
ENSE00001380031	11556511	11556735
ENSE00002642076	11586886	11586919
ENSE00003463715	11553533	11553689
ENSE00004035163	11547722	11549745

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 192.4688 / max 9578.1269, expressed in 1775 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
156281	157.4237	1747
156282	24.0097	1706
156283	5.3822	1400
156285	1.1014	661
156273	1.0670	472
156275	0.8818	421
156274	0.8284	371
156287	0.5643	265
156296	0.2180	97
156280	0.2109	76

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	99.56	gold quality
palpebral conjunctiva	UBERON:0001812	99.55	gold quality
periodontal ligament	UBERON:0008266	99.36	gold quality
visceral pleura	UBERON:0002401	98.69	gold quality
mucosa of urinary bladder	UBERON:0001259	98.62	gold quality
vermiform appendix	UBERON:0001154	98.50	gold quality
tibia	UBERON:0000979	98.47	gold quality
granulocyte	CL:0000094	98.44	gold quality
endocervix	UBERON:0000458	98.35	gold quality
gall bladder	UBERON:0002110	98.30	gold quality
colonic mucosa	UBERON:0000317	98.15	gold quality
stromal cell of endometrium	CL:0002255	98.09	gold quality
endometrium epithelium	UBERON:0004811	98.08	gold quality
amniotic fluid	UBERON:0000173	98.05	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.05	gold quality
caecum	UBERON:0001153	98.01	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.01	gold quality
upper lobe of left lung	UBERON:0008952	97.95	gold quality
rectum	UBERON:0001052	97.92	gold quality
bone marrow	UBERON:0002371	97.85	gold quality
olfactory bulb	UBERON:0002264	97.84	gold quality
upper lobe of lung	UBERON:0008948	97.84	gold quality
right coronary artery	UBERON:0001625	97.82	gold quality
renal medulla	UBERON:0000362	97.78	gold quality
right lung	UBERON:0002167	97.78	gold quality
trabecular bone tissue	UBERON:0002483	97.67	gold quality
metanephric glomerulus	UBERON:0004736	97.67	gold quality
left coronary artery	UBERON:0001626	97.62	gold quality
pleura	UBERON:0000977	97.55	gold quality
lymph node	UBERON:0000029	97.54	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-MTAB-9221	yes	3419.77
E-CURD-120	yes	563.60
E-MTAB-6911	yes	327.34
E-HCAD-4	yes	110.44
E-HCAD-1	yes	84.43
E-CURD-122	yes	55.84
E-MTAB-5061	yes	27.83
E-GEOD-81547	yes	25.76
E-GEOD-125970	yes	22.73
E-CURD-46	yes	22.34
E-GEOD-93593	yes	19.87
E-CURD-88	yes	16.55
E-HCAD-9	yes	16.28
E-MTAB-8410	yes	13.16
E-GEOD-83139	yes	12.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

28 targets.

Target	Regulation
ACHE
APOA2
BRAF
FGF10
FURIN
GADD45A
GAP43
GFM1
H2AC18
HSPA5
IRF6
KRT8
LITAF
MAFG
MAPK1
MAPK14
MCAT
MDM2
MLANA
MRPL41
MYD88
NFKB
PIK3R1
TNF	Activation
TNFSF15	Activation
TP53
TPM1
VEGFA	Activation

Upstream regulators (CollecTRI, top): ATF4, BCL6, DDIT3, ESR1, FOS, IRF3, IRF6, LITAF, MAFG, NCOR2, NR2F2, RUNX1, SP1, TBP, TCF3, TP53, USF1, WT1

miRNA regulators (miRDB)

79 targeting LITAF, 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-5193	100.00	67.26	1744
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-609	99.82	64.26	505
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• New gene for CMT is located on chrosome 16. (PMID:14641644)
• The expression of SIMPLE is reported in various cell types of the sciatic nerve, including Schwann cells, the affected cell type in Charcot-Marie-Tooth neuropathy type 1C. (PMID:15122712)
• the potential E3 ubiquitin ligase activity of SIMPLE, alteration in its interactions with NEDD4 or TSG101, or changes in its properties as a clathrin coat adaptor may underlie the pathogenesis of Charcot-Marie-Tooth disease (PMID:15776429)
• This study identified a LITAF/SIMPLE substitution (T49M), absent in 1000 control chromosomes, but which was thought to be a polymorphism in Charcot-Marie-Tooth neuropathy. (PMID:16373087)
• The mutation Gly112Ser was found in two families confirming its frequent occurrence in SIMPLE mutations. Three novel mutations were also identified: Ala111Gly (two families), Pro135Ser, and Pro135Thr. (PMID:16787513)
• LITAF has a role in the pathophysiological regulation of the TNF-alpha gene (PMID:16804395)
• results suggest that the consensus sequence for hepatocyte nuclear factor-3alpha, or a nuclear binding protein to the CTCCC motif, may play an important role in regulating LPS-dependent LITAF transcription (PMID:16872372)
• Hypermethylation of pig7 promoter was identified in K562 and HL-60 cells, in contrast to non-methylation predominant in U937 cells. pig7 expression was markedly decreased in AL patients. (PMID:18078129)
• Two sequence variations c.269G–>A and c.274A–>G were detected in LITAF gene and two sequence variations c.1243G–>A and c.1910C–>T were detected in LMNA gene in Chinese Charcot-Marie-Tooth disease. (PMID:20709679)
• Lipopolysaccharide-induced tumor necrosis factor (LITAF) interacted with CIDE-3 in hepatic cells. (PMID:20957525)
• studies for the first time establish the regulatory axis of AMPK-LITAF-TNFSF15 and also suggest that LITAF may function as a tumor suppressor (PMID:21217782)
• Itch protein re-localization is dependent upon the interaction with the PPXY sequences of LITAF, since disruption of these binding motifs completely abrogates Itch re-localization. (PMID:21326863)
• LITAF is associated with obesity and insulin resistance, as well as inflammatory cytokine secretion. The results indicate LITAF to be a new mediator between inflammation and the obesity related disorders. (PMID:21362361)
• PIG7 could be transactivated by AML1, which subsequently induces differentiation and apoptosis of leukemia cells, especially those with AML1-ETO fusion gene (PMID:21836606)
• Our findings suggest that SIMPLE mutations cause Charcot-Marie-Tooth type 1 C peripheral neuropathy by a combination of loss-of-function and toxic gain-of-function mechanisms (PMID:21896645)
• It is concluded that PA can induce insulin resistance in liver cells and knockdown of LITAF expression can reduce insulin resistance in liver cells. (PMID:22282245)
• The findings indicate a function of SIMPLE as a regulator of endosomal trafficking and provide evidence linking dysregulated endosomal trafficking to CMT pathogenesis. (PMID:23166352)
• Mutation of SIMPLE (Litaf) in Charcot-Marie-Tooth 1C disease alters production of exosomes. (PMID:23576546)
• LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas. (PMID:23795761)
• Early-onset hereditary neuropathy with liability to pressure palsy (HNPP) was associated frequently with isoleucine92valine LITAF polymorphism. (PMID:24668782)
• The results of this study findings confirm that the genetic analysis of LITAF/SIMPLE should be considered for the diagnostic flow-chart of CMT1 patient, especially when nerve conduction studies show the presence of conduction blocks. (PMID:24880540)
• Results show that LITAF mutants in Charcot-Marie-Tooth 1C have an altered intracellular localization. They localize either completely or partially in the mitochondria depending on the mutation site. This can explain the different severity of the disease. (PMID:25058650)
• Study shows that the I92V LITAF sequence variant would be a good candidate for a biomarker in the case of the CMT1A/HNPP disorders. (PMID:25342198)
• LITAF may serve as a switch in the balance between classical and alternative activation in tumor-associated inflammation. (Review) (PMID:26324337)
• Suggest LITAF as regulatory of pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease. (PMID:26573228)
• PIG7 promotes leukemia cell chemosensitivity via lysosomal membrane permeabilization. (PMID:26716897)
• Study conclude that LITAF is a monotopic membrane protein whose membrane integration is stabilised by a zinc finger. The related human protein, CDIP1 (cell death involved p53 target 1), displays identical membrane topology, suggesting that this mode of membrane integration is conserved in LITAF family proteins. (PMID:27582497)
• our findings provide a novel apoptotic regulatory pathway in which LITAF, as a transcription factor, inhibits the expression of BCL6, which leads to activation of the intrinsic mitochondrial pathway and tumor apoptosis. (PMID:27764808)
• In this Chinese Han population a novel Charcot-Marie-Tooth disease-associated gene mutations the LITAF (c.32C>G) was discovered. (PMID:27862672)
• An aberrant LITAF-phosphoethanolamine interaction on the surface of intracellular membranes contributes to the molecular pathogenesis that underlies Charcot-Marie-Tooth disease type 1C. (PMID:27927196)
• The Gly112Ser mutation causing Charcot-Marie-Tooth disease type 1C is a mild form of Charcot-Marie-Tooth disease. (PMID:28164329)
• Molecular analysis of Charcot-Marie-Tooth 1C revealed five new LITAF/SIMPLE mutations (PMID:28211240)
• miR-106a was significantly elevated in high-grade human prostate tumors relative to intermediate- and low-grade specimens. An inverse correlation was seen with its target, LITAF. Furthermore, high miR-106a and low LITAF expression predict for biochemical recurrence at 5 years after radical prostatectomy. (PMID:29845714)
• results indicate that SIMPLE may regulate protein trafficking physiologically by localizing to the TGN and/or REs by binding PI4P. (PMID:29953492)
• The authors show that WDR86-AS1, miR-10b-3p, and LITAF are involved in preeclampsia pathogenesis. (PMID:30552989)
• LITAF expression is decreased in glioma tissues and might enhance radiosensitivity of glioma cells via upregulation of the FoxO1 pathway. (PMID:31098771)
• Involvement of the MicroRNA-1-LITAF Axis in Gastric Cancer Cell Growth and Invasion. (PMID:33109562)
• Atypical presentation of Charcot-Marie-Tooth disease type 1C with a new mutation: a case report. (PMID:34311727)
• SIMPLE Is an Endosomal Regulator That Protects Against NAFLD by Targeting the Lysosomal Degradation of EGFR. (PMID:34320238)
• Identification and clinical characterization of Charcot-Marie-Tooth disease type 1C patients with LITAF p.G112S mutation. (PMID:35608774)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	litaf	ENSDARG00000103483
mus_musculus	Litaf	ENSMUSG00000022500
rattus_norvegicus	Litaf	ENSRNOG00000002520
drosophila_melanogaster	CG12645	FBGN0030181
drosophila_melanogaster	CG13510	FBGN0034758
drosophila_melanogaster	CG4250	FBGN0034761
drosophila_melanogaster	CG13516	FBGN0040658
drosophila_melanogaster	CG30269	FBGN0050269
drosophila_melanogaster	CG30273	FBGN0050273
caenorhabditis_elegans		WBGENE00012548
caenorhabditis_elegans		WBGENE00012748
caenorhabditis_elegans		WBGENE00017513
caenorhabditis_elegans		WBGENE00021253
caenorhabditis_elegans	Y87G2A.19	WBGENE00044260

Paralogs (1): CDIP1 (ENSG00000089486)

Protein

Protein identifiers

Lipopolysaccharide-induced tumor necrosis factor-alpha factor — Q99732 (reviewed: Q99732)

Alternative names: Small integral membrane protein of lysosome/late endosome, p53-induced gene 7 protein

All UniProt accessions (13): A0A0G2JLC4, I3L133, I3L1H3, I3L1I9, I3L1P1, I3L1R0, I3L2E2, I3L2T1, I3L2T6, I3L329, I3L3U8, Q99732, I3L409

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in endosomal protein trafficking and in targeting proteins for lysosomal degradation. Plays a role in targeting endocytosed EGFR and ERGG3 for lysosomal degradation, and thereby helps down-regulate downstream signaling cascades. Helps recruit the ESCRT complex components TSG101, HGS and STAM to cytoplasmic membranes. Probably plays a role in regulating protein degradation via its interaction with NEDD4. May also contribute to the regulation of gene expression in the nucleus. Binds DNA (in vitro) and may play a synergistic role with STAT6 in the nucleus in regulating the expression of various cytokines. May regulate the expression of numerous cytokines, such as TNF, CCL2, CCL5, CXCL1, IL1A and IL10.

Subunit / interactions. Monomer. Interacts with NEDD4. Interacts (via PSAP motif) with TSG101, a component of the ESCRT-I complex (endosomal sorting complex required for transport I). Interacts with WWOX. Interacts with STAM, a component of the ESCRT-0 complex; the interaction is direct. Identified in a complex with STAM and HGS; within this complex, interacts directly with STAM, but not with HGS. Interacts with STAT6.

Subcellular location. Cytoplasm. Nucleus. Lysosome membrane. Early endosome membrane. Late endosome membrane. Endosome membrane. Cell membrane. Golgi apparatus membrane.

Tissue specificity. Ubiquitously and abundantly expressed. Expressed predominantly in the placenta, peripheral blood leukocytes, lymph nodes and spleen.

Post-translational modifications. Phosphorylated on tyrosine residues in response to EGF.

Disease relevance. Charcot-Marie-Tooth disease, demyelinating, type 1C (CMT1C) [MIM:601098] A dominant demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. The disease is caused by variants affecting the gene represented in this entry. Defects in LITAF may be involved in extramammary Paget disease (EMPD) carcinogenesis. EMPD is a cancerous disease representing about 8% of all malignant skin cancers; it usually appears in the anogenital area and can be fatal by metastasizing to internal organs when left untreated for a long time. The clinical features are usually those of eczematous eruptions with weeping and crust formation.

Domain organisation. The PPxY motif mediates interaction with WWOX and NEDD4. The LITAF domain is stabilized by a bound zinc ion. The LITAF domain contains an amphipathic helix that mediates interaction with lipid membranes. It interacts specifically with phosphatidylethanolamine lipid headgroups, but not with phosphoglycerol, phosphocholine, phosphoserine or inositolhexakisphosphate.

Induction. Up-regulated by bacterial lipopolysaccharide (LPS) (at protein level). By bacterial lipopolysaccharide (LPS) and by p53/TP53. In monocytes by the Bacillus Calmette-Guerin (BCG).

Miscellaneous. May be due to a frameshift that creates an unconventional splicing site. Data inferred from this isoform must be interpreted with caution.

Similarity. Belongs to the CDIP1/LITAF family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q99732-1	1	yes
Q99732-2	2
Q99732-3	3

RefSeq proteins (3): NP_001129944, NP_001129945, NP_004853 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006629	LITAF	Domain
IPR037519	LITAF_fam	Family

Pfam: PF10601

UniProt features (29 total): mutagenesis site 9, sequence variant 8, binding site 4, splice variant 2, region of interest 2, short sequence motif 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99732-F1	70.60	0.27

Functional residue map

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

Ligand- & substrate-binding residues (4): 96; 99; 148; 151

Mutagenesis-validated functional residues (9):

Position	Phenotype
17–20	impaired function in targeting endocytosed proteins for lysosomal degradation.
17–19	abolishes interaction with tsg101.
23	abolishes interaction with nedd4.
23	abolishes interaction with wwox. abolishes interaction with nedd4. abolishes interaction with nedd4 and impairs location
61	no effect on interaction with wwox. no effect on interaction with nedd4. abolishes interaction with nedd4 and impairs lo
96	abolishes association with cytoplasmic vesicle membranes.
135	decreases protein stability and association with early endosome membranes. impaired function in targeting endocytosed pr
144	no effect on location at endosomes, but impairs protein stability.
148	abolishes association with cytoplasmic vesicle membranes.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 479 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, DAVIES_MULTIPLE_MYELOMA_VS_MGUS_DN, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, BASSO_B_LYMPHOCYTE_NETWORK, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOCC_VACUOLAR_MEMBRANE, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOLDRATH_ANTIGEN_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, HINATA_NFKB_TARGETS_KERATINOCYTE_UP

GO Biological Process (7): regulation of cytokine production (GO:0001817), regulation of macrophage cytokine production (GO:0010935), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of transcription by RNA polymerase II (GO:0045944), cellular response to lipopolysaccharide (GO:0071222), negative regulation of non-canonical NF-kappaB signal transduction (GO:1901223), response to lipopolysaccharide (GO:0032496)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), WW domain binding (GO:0050699), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (17): Golgi membrane (GO:0000139), nucleus (GO:0005634), nucleoplasm (GO:0005654), lysosomal membrane (GO:0005765), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), cytoplasmic side of plasma membrane (GO:0009898), cytoplasmic side of early endosome membrane (GO:0098559), cytoplasmic side of late endosome membrane (GO:0098560), cytoplasmic side of lysosomal membrane (GO:0098574), cytoplasm (GO:0005737), lysosome (GO:0005764), endosome (GO:0005768), endosome membrane (GO:0010008), membrane (GO:0016020), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
bounding membrane of organelle	2
intracellular membrane-bounded organelle	2
endomembrane system	2
cytoplasmic side of membrane	2
cytoplasmic side of endosome membrane	2
endosome membrane	2
cytokine production	1
regulation of gene expression	1
regulation of multicellular organismal process	1
regulation of cytokine production involved in immune response	1
macrophage cytokine production	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
non-canonical NF-kappaB signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
cis-regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transition metal ion binding	1
protein binding	1
protein domain specific binding	1
nucleic acid binding	1
binding	1
cation binding	1
Golgi apparatus	1

Protein interactions and networks

STRING

1436 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LITAF	RNMT	O43148	870
LITAF	EMP2	P54851	763
LITAF	SH3TC2	Q8TF17	705
LITAF	TSG101	Q99816	660
LITAF	FIG4	Q92562	647
LITAF	GDAP1	Q8TB36	625
LITAF	MTMR2	Q13614	603
LITAF	GJB1	P08034	602
LITAF	SBF2	Q86WG5	571
LITAF	RNF207	Q6ZRF8	571
LITAF	STAM	Q92783	565
LITAF	NEDD4	P46934	558
LITAF	WWOX	Q9NZC7	548
LITAF	IL1B	P01584	543
LITAF	IL6	P05231	542

IntAct

259 interactions, top by confidence:

A	B	Type	Score
STAM2	LITAF	psi-mi:“MI:0915”(physical association)	0.850
LITAF	STAM2	psi-mi:“MI:0915”(physical association)	0.850
BAG3	LITAF	psi-mi:“MI:0915”(physical association)	0.780
LITAF	HGS	psi-mi:“MI:0915”(physical association)	0.780
REEP6	LITAF	psi-mi:“MI:0915”(physical association)	0.780
LITAF	BAG3	psi-mi:“MI:0915”(physical association)	0.780
HGS	LITAF	psi-mi:“MI:0915”(physical association)	0.780
LITAF	REEP6	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (119): LITAF (Two-hybrid), BAG3 (Two-hybrid), CALCOCO2 (Two-hybrid), STAM2 (Two-hybrid), UBQLN1 (Two-hybrid), REEP6 (Two-hybrid), TSG101 (Affinity Capture-Western), NEDD4 (Affinity Capture-Western), NEDD4L (Affinity Capture-Western), ITCH (Affinity Capture-Western), WWP1 (Affinity Capture-Western), WWP2 (Affinity Capture-Western), TOM1 (Affinity Capture-Western), TAB2 (Affinity Capture-Western), CALCOCO2 (Two-hybrid)

ESM2 similar proteins: B6SGC5, O95415, P0C0T0, P28662, P50636, Q32L83, Q3C2P8, Q3T0A9, Q3TWL2, Q4R5H7, Q4R6W2, Q58D45, Q5BJ83, Q5E9E8, Q5EAU3, Q5F3S2, Q5PPK1, Q5PPM8, Q5PQS5, Q5R4K6, Q5RDN2, Q5U2U6, Q5XID0, Q5XKA6, Q5Y171, Q66I51, Q66JG9, Q6DC04, Q6DIE4, Q6GMG8, Q6NYG4, Q6NYK3, Q6P828, Q7Z698, Q7Z699, Q86T03, Q8AVW3, Q8N114, Q8QGW7, Q8VIH7

Diamond homologs: A0A1B0GVX0, P0C0T0, Q54HX8, Q6GMG8, Q6GZQ0, Q6P828, Q8QGW7, Q99732, Q9JLJ0, Q58D45, Q5BJ83, Q5U2U6, Q8AVW3, Q9DB75, Q9H305

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
BCL6	“down-regulates quantity by repression”	LITAF	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 61 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
EGFR downregulation	5	46.8×	1e-05
Cargo recognition for clathrin-mediated endocytosis	8	22.6×	8e-07
Clathrin-mediated endocytosis	7	16.1×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
regulation of signal transduction	6	27.7×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	3
Uncertain significance	156
Likely benign	67
Benign	52

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
41229	NM_001136472.2(LITAF):c.332C>G (p.Ala111Gly)	Pathogenic
41230	NM_001136472.2(LITAF):c.403C>A (p.Pro135Thr)	Pathogenic
6057	NM_001136472.2(LITAF):c.334G>A (p.Gly112Ser)	Pathogenic
6059	NM_001136472.2(LITAF):c.346T>G (p.Trp116Gly)	Pathogenic
6060	NM_001136472.2(LITAF):c.364C>G (p.Leu122Val)	Pathogenic
1526424	NM_001136472.2(LITAF):c.232A>T (p.Thr78Ser)	Likely pathogenic
1526503	GRCh37/hg19 16p13.13(chr16:11632852-11714575)	Likely pathogenic
2502274	NM_001136472.2(LITAF):c.403C>G (p.Pro135Ala)	Likely pathogenic

SpliceAI

1078 predictions. Top by Δscore:

Variant	Effect	Δscore
16:11549746:CTGG:C	acceptor_loss	1.0000
16:11549747:T:A	acceptor_loss	1.0000
16:11553527:ACTC:A	donor_loss	1.0000
16:11553528:CTCA:C	donor_loss	1.0000
16:11553529:TCA:T	donor_loss	1.0000
16:11553530:CA:C	donor_loss	1.0000
16:11553531:A:AC	donor_gain	1.0000
16:11553531:AC:A	donor_gain	1.0000
16:11553531:ACC:A	donor_gain	1.0000
16:11553532:C:CC	donor_gain	1.0000
16:11553532:CC:C	donor_gain	1.0000
16:11553532:CCC:C	donor_gain	1.0000
16:11553687:TAA:T	acceptor_gain	1.0000
16:11553688:AAC:A	acceptor_loss	1.0000
16:11553690:C:CC	acceptor_gain	1.0000
16:11553693:A:AC	acceptor_gain	1.0000
16:11553693:A:C	acceptor_gain	1.0000
16:11587395:T:TA	donor_gain	1.0000
16:11549743:CAC:C	acceptor_gain	0.9900
16:11553526:GACT:G	donor_loss	0.9900
16:11553685:GGTAA:G	acceptor_gain	0.9900
16:11553686:GTAA:G	acceptor_gain	0.9900
16:11553688:AA:A	acceptor_gain	0.9900
16:11556509:A:AC	donor_gain	0.9900
16:11556510:C:CC	donor_gain	0.9900
16:11556571:T:TA	donor_gain	0.9900
16:11556572:C:A	donor_gain	0.9900
16:11556638:A:C	donor_gain	0.9900
16:11587316:T:TA	donor_gain	0.9900
16:11549741:TGCAC:T	acceptor_gain	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000003111 (16:11581198 A>C,G), RS1000010037 (16:11559080 T>C), RS1000027042 (16:11641986 T>C), RS1000048456 (16:11593739 A>G), RS1000079006 (16:11641755 T>G), RS1000093405 (16:11619436 C>T), RS1000104778 (16:11577484 G>C), RS1000107457 (16:11610689 G>A), RS1000165627 (16:11611829 GT>G), RS1000193595 (16:11631927 G>A), RS1000246050 (16:11638275 A>G), RS1000294460 (16:11606624 C>A,G,T), RS1000295549 (16:11636868 A>C,T), RS1000298355 (16:11638484 C>A,T), RS1000312753 (16:11597902 T>C)

Disease associations

OMIM: gene MIM:603795 | disease phenotypes: MIM:601098, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease type 1C	Strong	Autosomal dominant
Charcot-Marie-Tooth disease	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease	Moderate	AD

Mondo (5): Charcot-Marie-Tooth disease type 1C (MONDO:0010995), Charcot-Marie-Tooth disease (MONDO:0015626), hereditary ataxia (MONDO:0100309), distal hereditary motor neuropathy (MONDO:0018894), Charcot-Marie-Tooth disease type 1 (MONDO:0019011)

Orphanet (5): Charcot-Marie-Tooth disease type 1C (Orphanet:101083), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Hereditary ataxia (Orphanet:183518), Distal hereditary motor neuropathy (Orphanet:53739), Charcot-Marie-Tooth disease type 1 (Orphanet:65753)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000762	Decreased nerve conduction velocity
HP:0001251	Ataxia
HP:0001265	Hyporeflexia
HP:0001271	Polyneuropathy
HP:0001761	Pes cavus
HP:0002066	Gait ataxia
HP:0002403	Positive Romberg sign
HP:0002460	Distal muscle weakness
HP:0002936	Distal sensory impairment
HP:0003382	Hypertrophic nerve changes
HP:0003383	Onion bulb formation
HP:0003401	Paresthesia
HP:0003431	Decreased motor nerve conduction velocity
HP:0003481	Segmental peripheral demyelination/remyelination
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0003693	Distal amyotrophy
HP:0007141	Sensorimotor neuropathy
HP:0007230	Decreased distal sensory nerve action potential
HP:0033748	Hypoesthesia

GWAS associations

99 associations (top):

Study	Trait	p-value
GCST000363_8	QT interval	5.000000e-15
GCST000364_10	QT interval	6.000000e-15
GCST001725_27	Inflammatory bowel disease	2.000000e-16
GCST001746_17	QT interval	7.000000e-07
GCST002363_2	Response to anti-retroviral therapy (ddI/d4T) in HIV-1 infection (Grade 3 peripheral neuropathy)	6.000000e-06
GCST002500_13	QT interval	2.000000e-28
GCST002500_14	QT interval	2.000000e-12
GCST002500_25	QT interval	3.000000e-13
GCST003208_12	Colorectal or endometrial cancer	3.000000e-06
GCST004131_115	Inflammatory bowel disease	1.000000e-06
GCST004132_39	Crohn’s disease	1.000000e-07
GCST005038_94	Allergic disease (asthma, hay fever or eczema)	6.000000e-09
GCST005171_52	QT interval	6.000000e-13
GCST006979_247	Heel bone mineral density	8.000000e-25
GCST007209_17	Gallstone disease	4.000000e-10
GCST007218_4	QT interval	3.000000e-11
GCST010204_214	Low density lipoprotein cholesterol levels	7.000000e-14
GCST010245_38	LDL cholesterol levels	8.000000e-09
GCST010346_59	TPE interval (resting)	6.000000e-09
GCST010796_1200	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-66
GCST010796_1251	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-48
GCST010796_1252	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-46
GCST010796_1253	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-44
GCST010796_1254	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-42
GCST010796_1255	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-39
GCST010796_1256	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-33
GCST010796_1257	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-31
GCST010796_1258	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-29
GCST010796_1259	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-26
GCST010796_1260	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-22

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0000180	HIV-1 infection
EFO:0004230	endometrial neoplasm
EFO:0009270	heel bone mineral density
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004644	TPE interval measurement
EFO:0004327	electrocardiography
EFO:0007989	monocyte percentage of leukocytes
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
C537984	Charcot-Marie-Tooth disease, Type 1C (supp.)
C531684	Hereditary spinal ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066581 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

62 measured of 62 human assays (63 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-[3-(3-chlorophenyl)-7-methoxy-2,4-dioxo-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinolin-1-yl]-N-propan-2-ylpiperidine-1-carboxamide	IC50	0.3 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
BDBM287835	IC50	0.3 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(3-chlorophenyl)-7-methoxy-1-(1-propan-2-ylsulfonylpiperidin-4-yl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	0.4 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
4-[3-(3-chlorophenyl)-7-methoxy-2,4-dioxo-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinolin-1-yl]-N,N-dimethylpiperidine-1-sulfonamide	IC50	0.4 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(3-chlorophenyl)-1-[1-(1,1-dioxothiolan-3-yl)sulfonylpiperidin-4-yl]-7-methoxy-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	0.4 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
4-[3-(3-chlorophenyl)-7-methoxy-2,4-dioxo-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinolin-1-yl]-N-ethylpiperidine-1-carboxamide	IC50	0.6 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(4-chlorophenyl)-7-methoxy-1-(4-methylcyclohexyl)-4aH-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	0.9 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
7-methoxy-1-(4-methylcyclohexyl)-3-(3-methylphenyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	1 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-butyl-7-methoxy-3-(3-methylphenyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	1 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
tert-butyl 4-[3-(3-chlorophenyl)-7-methoxy-2,4-dioxo-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinolin-1-yl]piperidine-1-carboxylate	IC50	1 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-(1-benzoylpiperidin-4-yl)-3-(3-chlorophenyl)-7-methoxy-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	1 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-[1-(benzenesulfonyl)piperidin-4-yl]-3-(3-chlorophenyl)-7-methoxy-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	1 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
tert-butyl 4-[3-(1,3-benzodioxol-5-yl)-7-methoxy-2,4-dioxo-4aH-pyrimido[5,4-c]quinolin-1-ium-1-yl]piperidine-1-carboxylate	IC50	1 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(3-chlorophenyl)-1-(4,4-difluorocyclohexyl)-7-methoxy-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	2 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-(1-acetylpiperidin-4-yl)-3-(3-chlorophenyl)-7-methoxy-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	2 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
tert-butyl (3S)-3-[3-(3-chlorophenyl)-7-methoxy-2,4-dioxo-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinolin-1-yl]pyrrolidine-1-carboxylate	IC50	2 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(3-chlorophenyl)-7-methoxy-1-[(1-methylsulfonylpiperidin-4-yl)methyl]-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	2 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(3-chlorophenyl)-7-methoxy-1-(4-methylcyclohexyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	4 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(3-chlorophenyl)-1-cyclohexyl-7-methoxy-4aH-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	4 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(3-chlorophenyl)-7-methoxy-1-piperidin-4-yl-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	5 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-cyclopentyl-3-(3-ethylphenyl)-7-methoxy-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	6 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(1,3-benzodioxol-5-yl)-7-methoxy-1-(1-methylsulfonylpiperidin-4-yl)-4aH-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	8 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(3-chlorophenyl)-1-cyclopentyl-7-methoxy-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	9 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(2-chlorophenyl)-7-methoxy-1-(4-methylcyclohexyl)-4aH-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	20 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(3-chlorophenyl)-7-methoxy-1-[(3R)-pyrrolidin-3-yl]-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	31 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
4-[3-(3-chlorophenyl)-7-methoxy-2,4-dioxo-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinolin-1-yl]cyclohexane-1-carboxylic acid	IC50	55 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
N-[4-[3-(3-chlorophenyl)-7-methoxy-2,4-dioxo-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinolin-1-yl]cyclohexyl]methanesulfonamide	IC50	73 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-cyclopentyl-7-methoxy-3-(3-methylsulfanylphenyl)-4aH-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	74 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(1-cyclopentyl-7-methoxy-2,4-dioxo-4aH-pyrimido[5,4-c]quinolin-1-ium-3-yl)benzonitrile	IC50	123 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(3-chlorophenyl)-7-methoxy-1-(1-methylsulfonylpiperidin-4-yl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	151 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(3-chlorophenyl)-7-methoxy-1-[(3R)-1-methylsulfonylpyrrolidin-3-yl]-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	163 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-cyclopentyl-7-methoxy-3-(4-methylphenyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	163 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-cyclopentyl-3-ethyl-7-methoxy-7H-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	180 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-ethyl-7-methoxy-1-(4-methylcyclohexyl)-7H-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	200 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(3-chlorophenyl)-7-methoxy-1-[(3S)-1-methylsulfonylpyrrolidin-3-yl]-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	206 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-cyclopentyl-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-methoxy-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	240 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-cyclopentyl-7-methoxy-3-propan-2-yl-4aH-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	270 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-cyclopentyl-7-methoxy-3-(3-methylsulfonylphenyl)-4aH-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	280 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-cyclopentyl-7-methoxy-3-(3-methylphenyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	338 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-butyl-3-ethyl-7-methoxy-7H-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	390 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-cyclopentyl-7-methoxy-3-thiophen-2-yl-7H-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	410 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-butan-2-yl-1-cyclopentyl-7-methoxy-7H-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	450 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(1,3-benzodioxol-5-yl)-7-methoxy-1-piperidin-4-yl-4aH-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	450 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-cyclopentyl-3-ethyl-7-methylidenepyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	500 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-cyclopentyl-7-methoxy-3-(4-methylthiophen-2-yl)-7H-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	616 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-ethyl-7-methoxy-1-propyl-7H-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	680 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-(1,3-benzodioxol-5-yl)-1-cyclopentyl-7-methoxy-4a,5,6,6a,7,8,9,10,10a,10b-decahydropyrimido[5,4-c]quinoline-2,4-dione	IC50	827 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
3-ethyl-1-(3-fluoropropyl)-7-methoxy-7H-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	900 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
1-cyclopentyl-3-ethyl-9-fluoro-7-methoxy-7H-pyrimido[5,4-c]quinolin-1-ium-2,4-dione	IC50	920 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors
ethyl 2-(1-cyclopentyl-7-methoxy-2,4-dioxo-7H-pyrimido[5,4-c]quinolin-1-ium-3-yl)acetate	IC50	1000 nM	US-9393245: Tricyclic compounds as modulators of TNF-alpha synthesis and as PDE4 inhibitors

ChEMBL bioactivities

58 potent at pChembl≥5 of 62 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.52	IC50	0.3	nM	CHEMBL3954709
9.52	IC50	0.3	nM	CHEMBL4108792
9.40	IC50	0.4	nM	CHEMBL3955760
9.40	IC50	0.4	nM	CHEMBL3932863
9.40	IC50	0.4	nM	CHEMBL3938364
9.22	IC50	0.6	nM	CHEMBL3971431
9.05	IC50	0.9	nM	CHEMBL3911773
9.00	IC50	1	nM	CHEMBL3958848
9.00	IC50	1	nM	CHEMBL3972551
9.00	IC50	1	nM	CHEMBL3966151
9.00	IC50	1	nM	CHEMBL3931657
9.00	IC50	1	nM	CHEMBL3960339
9.00	IC50	1	nM	CHEMBL3938524
9.00	IC50	1	nM	CHEMBL3962096
8.70	IC50	2	nM	CHEMBL3644500
8.70	IC50	2	nM	CHEMBL3921402
8.70	IC50	2	nM	CHEMBL3976439
8.70	IC50	2	nM	CHEMBL3903807
8.70	IC50	2	nM	CHEMBL3986640
8.62	IC50	2.4	nM	CHEMBL3644501
8.40	IC50	4	nM	CHEMBL3986436
8.40	IC50	4	nM	CHEMBL3948031
8.30	IC50	5	nM	CHEMBL3947142
8.22	IC50	6	nM	CHEMBL3644499
8.22	IC50	6	nM	CHEMBL3932267
8.22	IC50	6	nM	CHEMBL3945875
8.10	IC50	8	nM	CHEMBL3986932
8.05	IC50	9	nM	CHEMBL3913144
7.70	IC50	20	nM	CHEMBL3962756
7.54	IC50	29	nM	CHEMBL3644503
7.54	IC50	29	nM	CHEMBL3644504
7.52	IC50	30	nM	CHEMBL3644498
7.51	IC50	31	nM	CHEMBL4110900
7.13	IC50	74	nM	CHEMBL3982748
6.91	IC50	123	nM	CHEMBL3964458
6.79	IC50	163	nM	CHEMBL3925334
6.75	IC50	180	nM	CHEMBL3952484
6.70	IC50	200	nM	CHEMBL3944621
6.62	IC50	240	nM	CHEMBL3958464
6.57	IC50	270	nM	CHEMBL3894945
6.55	IC50	280	nM	CHEMBL3953457
6.41	IC50	390	nM	CHEMBL3969462
6.39	IC50	410	nM	CHEMBL3949836
6.35	IC50	450	nM	CHEMBL3938310
6.35	IC50	450	nM	CHEMBL3917179
6.30	IC50	500	nM	CHEMBL3984643
6.17	IC50	680	nM	CHEMBL3892871
6.05	IC50	900	nM	CHEMBL3936729
6.04	IC50	920	nM	CHEMBL3978166
6.00	IC50	1000	nM	CHEMBL3958223

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	5
methylmercuric chloride	increases expression, affects cotreatment	3
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	affects expression, increases expression	3
Resveratrol	decreases expression, increases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	3
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	2
Lipopolysaccharides	increases expression, affects response to substance	2
Tetrachlorodibenzodioxin	increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
4-hydroxyphenyl 4-isopropoxyphenylsulfone	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	increases expression	1
sulforaphane	increases expression	1
alpha-cobratoxin	increases expression, decreases expression, decreases reaction	1
nickel sulfate	decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
isobutyl alcohol	affects cotreatment, increases abundance, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
chloropicrin	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects cotreatment, increases expression	1
Rosiglitazone	affects cotreatment, increases expression, decreases reaction	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5731389	Binding	TNF inhibition assay: Samples were tested for TNF as per the manufacturer’s instructions (TNF ELISA; R&D Systems, Cat #DY210). The samples were serially diluted with PBS+1% BSA to the appropriate dilution condition for the cell prep, typica	Tricyclic compounds as modulators of TNF-α synthesis and as PDE4 inhibitors

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1821	Karpas-1106P	Cancer cell line	Female
CVCL_B1VV	Abcam HeLa LITAF KO	Cancer cell line	Female
CVCL_SV61	HAP1 LITAF (-) 1	Cancer cell line	Male
CVCL_SV62	HAP1 LITAF (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others
NCT01203085	Not specified	COMPLETED	Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT
NCT01455623	Not specified	COMPLETED	Development and Validation of a Disability Severity Index for CMT
NCT01918826	Not specified	UNKNOWN	Evaluation of the Analgesic Efficiency of the Transcutaneous Neurostimulation in the Charcot Syndrome Marie Tooth on the Pains of Lower Limbs
NCT02001038	Not specified	COMPLETED	Survey of Current Management of Orthopaedic Complications in CMT Patients
NCT02011204	Not specified	COMPLETED	Study of Electrical Impedance Myography (EIM) in ALS
NCT02194010	Not specified	COMPLETED	Disability Severity Scale (DSI) and Hereditary Motor and Sensory Neuropathy Overall Disability Scale (HMSN-R-ODS)
NCT02429947	Not specified	COMPLETED	An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients
NCT02532244	Not specified	COMPLETED	Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02788734	Not specified	COMPLETED	Patient Reported Outcomes Measures (PROM) in Carpal Tunnel Therapies in Patients With Inherited Neuropathies
NCT02979145	Not specified	UNKNOWN	Charcot-Marie-Tooth Disease (CMT) Infant Scale (INC-6611)
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03460951	Not specified	COMPLETED	Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy (PIDC)
NCT03715283	Not specified	COMPLETED	Change in MUNIX in Patients With CMT1A Undergoing a Home Ankle Strengthening Program Versus Standard of Care
NCT03782883	Not specified	COMPLETED	The Impact of Charcot-Marie-Tooth Disease in the Real World
NCT03810508	Not specified	TERMINATED	A Natural History Study of Charcot-Marie-Tooth 4J (CMT4J)
NCT03966287	Not specified	COMPLETED	Analysis of Pain and Quality of Life in Patients With Charcot-Marie-Tooth Neuropathy (CMT)
NCT04010188	Not specified	RECRUITING	A Registered Cohort Study on Charcot-Marie-Tooth Disease
NCT04283175	Not specified	COMPLETED	Validation Study of Posturology Platforms for Evaluating Postural Control of Hemiparetic and Neuro-muscular Patients
NCT04461613	Not specified	UNKNOWN	Physical Activity in Persons With Charcot-Marie-Tooth: Developing a Measurement Instrument
NCT04786522	Not specified	COMPLETED	Irisin Levels in Patients With Charcot-Marie-Tooth (CMT) Disease
NCT04967716	Not specified	UNKNOWN	Genetics of Charcot-Marie-Tooth Dystrophy and Related Diseases
NCT04980807	Not specified	COMPLETED	Observational Study of Neuromuscular Function in CMT Type 1&2 and Healthy Controls