TTI1

Summary

TTI1 (TELO2 interacting protein 1, HGNC:29029) is a protein-coding gene on chromosome 20q11.23, encoding TELO2-interacting protein 1 homolog (O43156). Regulator of the DNA damage response (DDR). It is a common-essential gene (DepMap: required in 94.6% of cancer cell lines).

Involved in positive regulation of DNA damage checkpoint and regulation of TOR signaling. Located in cytoplasm. Part of TORC1 complex; TORC2 complex; and TTT Hsp90 cochaperone complex.

Source: NCBI Gene 9675 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with microcephaly and movement abnormalities (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 242 total — 4 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 34
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 94.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_001303457

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29029
Approved symbol	TTI1
Name	TELO2 interacting protein 1
Location	20q11.23
Locus type	gene with protein product
Status	Approved
Aliases	smg-10
Ensembl gene	ENSG00000101407
Ensembl biotype	protein_coding
OMIM	614425
Entrez	9675

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000373447, ENST00000373448, ENST00000473288, ENST00000487362, ENST00000620381, ENST00000898962, ENST00000898963, ENST00000911389, ENST00000950416

RefSeq mRNA: 2 — MANE Select: NM_001303457 NM_001303457, NM_014657

CCDS: CCDS13300

Canonical transcript exons

ENST00000373447 — 8 exons

Exon	Start	End
ENSE00000661912	38006197	38006397
ENSE00000800521	38002628	38002776
ENSE00001460614	38011515	38013857
ENSE00001603770	38033404	38033456
ENSE00003529753	37996375	37996462
ENSE00003564439	37999188	37999328
ENSE00003601070	37996749	37996953
ENSE00003843464	37983021	37983639

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 89.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.9892 / max 58.5584, expressed in 1679 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187207	5.9192	1679
187206	0.0700	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	89.13	gold quality
cardia of stomach	UBERON:0001162	88.15	gold quality
embryo	UBERON:0000922	87.91	gold quality
endometrium epithelium	UBERON:0004811	87.79	silver quality
renal medulla	UBERON:0000362	87.60	gold quality
ganglionic eminence	UBERON:0004023	87.47	gold quality
oocyte	CL:0000023	87.46	gold quality
right uterine tube	UBERON:0001302	87.38	gold quality
sperm	CL:0000019	87.16	gold quality
ventricular zone	UBERON:0003053	86.76	gold quality
right lobe of thyroid gland	UBERON:0001119	86.66	gold quality
pylorus	UBERON:0001166	86.17	gold quality
left lobe of thyroid gland	UBERON:0001120	86.01	gold quality
paraflocculus	UBERON:0005351	85.99	silver quality
thyroid gland	UBERON:0002046	85.88	gold quality
body of pancreas	UBERON:0001150	85.72	gold quality
adrenal tissue	UBERON:0018303	85.62	gold quality
male germ cell	CL:0000015	85.27	gold quality
gastrocnemius	UBERON:0001388	85.22	gold quality
frontal pole	UBERON:0002795	85.20	silver quality
pancreas	UBERON:0001264	85.07	gold quality
seminal vesicle	UBERON:0000998	85.05	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.84	gold quality
middle frontal gyrus	UBERON:0002702	84.77	silver quality
muscle of leg	UBERON:0001383	84.59	gold quality
islet of Langerhans	UBERON:0000006	84.47	gold quality
pituitary gland	UBERON:0000007	84.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.37	gold quality
adenohypophysis	UBERON:0002196	84.01	gold quality
urethra	UBERON:0000057	84.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting TTI1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-5690	99.25	67.58	1012
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-4263	99.18	69.25	2236
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-4711-3P	98.97	66.87	1020
HSA-MIR-1-5P	98.70	68.66	1017
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-6792-5P	98.39	68.16	1330
HSA-MIR-581	98.39	67.42	835
HSA-MIR-147A	98.33	66.40	795
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-6818-5P	97.50	67.10	1167
HSA-MIR-6509-5P	97.39	68.27	969
HSA-MIR-6735-3P	96.10	63.81	600
HSA-MIR-4772-5P	95.60	68.04	617
HSA-MIR-6821-3P	95.21	66.79	578
HSA-MIR-1468-5P	94.18	69.04	176

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 94.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 7)

• Data show that that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. (PMID:20427287)
• TTI1 and TTI2 protect cells from spontaneous DNA damage, and are required for the establishment of the intra-S and G2/M checkpoin (PMID:20810650)
• IP7, formed by IP6K2, binds CK2 to enhance its phosphorylation of the Tti1/Tel2 complex, thereby stabilizing DNA-PKcs and ATM. This process stimulates p53 phosphorylation at serine 15 to activate the cell death program. (PMID:24657168)
• Structure of the Human TELO2-TTI1-TTI2 Complex. (PMID:34838521)
• TTI1 promotes non-small-cell lung cancer progression by regulating the mTOR signaling pathway. (PMID:36403197)
• Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly. (PMID:36724785)
• ALKBH5 promotes hepatocellular carcinoma cell proliferation, migration and invasion by regulating TTI1 expression. (PMID:38501918)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tti1	ENSDARG00000004114
mus_musculus	Tti1	ENSMUSG00000027650
rattus_norvegicus	Tti1	ENSRNOG00000012880
drosophila_melanogaster	Tti1	FBGN0037741
caenorhabditis_elegans		WBGENE00011225

Protein

Protein identifiers

TELO2-interacting protein 1 homolog — O43156 (reviewed: O43156)

Alternative names: Protein SMG10

All UniProt accessions (2): O43156, A0A087WT32

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of the DNA damage response (DDR). Part of the TTT complex that is required to stabilize protein levels of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family proteins. The TTT complex is involved in the cellular resistance to DNA damage stresses, like ionizing radiation (IR), ultraviolet (UV) and mitomycin C (MMC). Together with the TTT complex and HSP90 may participate in the proper folding of newly synthesized PIKKs. Promotes assembly, stabilizes and maintains the activity of mTORC1 and mTORC2 complexes, which regulate cell growth and survival in response to nutrient and hormonal signals.

Subunit / interactions. Component of the TTT complex composed of TELO2, TTI1 and TTI2. Interacts with ATM, ATR, MTOR, PRKDC, RUVBL1, SMG1, TELO2, TRRAP and TTI2. Component of the mTORC1 and mTORC2 complexes. Interacts with WAC; WAC positively regulates MTOR activity by promoting the assembly of the TTT complex and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex which leads to the dimerization of the mTORC1 complex and its subsequent activation.

Subcellular location. Cytoplasm.

Tissue specificity. Widely expressed.

Post-translational modifications. Phosphorylated at Ser-828 by CK2 following growth factor deprivation, leading to its subsequent ubiquitination by the SCF(FBXO9) complex. Phosphorylation by CK2 only takes place when TELO2 is bound to mTORC1, not mTORC2; leading to selective ubiquitination of mTORC1-associated protein. Ubiquitinated by the SCF(FBXO9) complex following phosphorylation by CK2 in response to growth factor deprivation, leading to its degradation by the proteasome. Only mTORC1-associated protein is ubiquitinated and degraded, leading to selective inactivation of mTORC1 to restrain cell growth and protein translation, while mTORC2 is activated due to the relief of feedback inhibition by mTORC1.

Disease relevance. Neurodevelopmental disorder with microcephaly and movement abnormalities (NEDMIM) [MIM:620445] An autosomal recessive disorder characterized by global developmental delay, impaired intellectual development with language impairment ranging from delayed speech to non-verbal, and delayed walking with an abnormal gait. Affected individuals may show hypotonia or hypertonia with spasticity, ataxia, and choreoathetoid movements. Most patients have microcephaly, non-specific dysmorphic features and short stature. Additional variable features include ocular defects, seizures, brain malformations, and skeletal defects. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the tti1 family.

RefSeq proteins (2): NP_001290386, NP_055472 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR016441	Tti1	Family
IPR049362	TTI1_rpt	Repeat
IPR052587	TELO2-interacting_protein_1	Family
IPR057566	TPR_TTI1_N	Domain
IPR057567	TPR_TTI1_C	Domain

Pfam: PF21547, PF24173, PF24176, PF24181

UniProt features (25 total): sequence variant 19, modified residue 2, chain 1, region of interest 1, compositionally biased region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7OLE	ELECTRON MICROSCOPY	3.41
7F4U	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43156-F1	81.38	0.44

Functional residue map

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

Post-translational modifications (2): 459, 828

Mutagenesis-validated functional residues (1):

Position	Phenotype
828	abolishes phosphorylation by ck2 in response to growth factor deprivation and subsequent ubiquitination and degradation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 238 (showing top): GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, MORF_MSH3, MORF_BRCA1, MORF_ATRX, GOBP_CELL_CYCLE_PHASE_TRANSITION, MORF_ESR1, YY1_Q6, COUP_01, PUJANA_CHEK2_PCC_NETWORK, MODULE_118, CCANNAGRKGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, MORF_PPP5C, MORF_FANCG

GO Biological Process (3): regulation of TOR signaling (GO:0032006), protein stabilization (GO:0050821), positive regulation of DNA damage checkpoint (GO:2000003)

GO Molecular Function (3): kinase binding (GO:0019900), protein-containing complex stabilizing activity (GO:0140777), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), TORC1 complex (GO:0031931), TORC2 complex (GO:0031932), TTT Hsp90 cochaperone complex (GO:0110078)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
TOR complex	2
TOR signaling	1
regulation of intracellular signal transduction	1
regulation of protein stability	1
DNA damage checkpoint signaling	1
positive regulation of cell cycle checkpoint	1
regulation of DNA damage checkpoint	1
enzyme binding	1
molecular_function	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
protein-containing complex	1

Protein interactions and networks

STRING

1184 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTI1	TELO2	Q9Y4R8	997
TTI1	TTI2	Q6NXR4	997
TTI1	DEPTOR	Q8TB45	996
TTI1	RICTOR	Q6R327	996
TTI1	MLST8	Q9BVC4	996
TTI1	MAPKAP1	Q9BPZ7	995
TTI1	RPTOR	Q8N122	993
TTI1	AKT1S1	Q96B36	993
TTI1	PRR5	P85299	992
TTI1	MTOR	P42345	939
TTI1	RUVBL1	P82276	798
TTI1	TRRAP	Q9Y4A5	756
TTI1	PIH1D1	Q9NWS0	717
TTI1	HSP90AA1	P07900	700
TTI1	HSP90AB1	P08238	700

IntAct

159 interactions, top by confidence:

A	B	Type	Score
TTI1	TELO2	psi-mi:“MI:0915”(physical association)	0.760
TELO2	TTI1	psi-mi:“MI:0915”(physical association)	0.760
TELO2	TTI1	psi-mi:“MI:0914”(association)	0.760
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
TTI1	RUVBL2	psi-mi:“MI:0914”(association)	0.690
TTI2	TTI1	psi-mi:“MI:0914”(association)	0.690
SCN2B	EXOC5	psi-mi:“MI:0914”(association)	0.640
CD68	TTI1	psi-mi:“MI:0914”(association)	0.640
VSIG1	TTI1	psi-mi:“MI:0914”(association)	0.640
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
FBXO9	TTI1	psi-mi:“MI:0914”(association)	0.610
FBXO9	TTI1	psi-mi:“MI:0915”(physical association)	0.610
TTI1	ATM	psi-mi:“MI:0915”(physical association)	0.610
ATM	TTI1	psi-mi:“MI:0915”(physical association)	0.610

BioGRID (189): ATM (Affinity Capture-Western), ATR (Affinity Capture-Western), PRKDC (Affinity Capture-Western), SMG1 (Affinity Capture-Western), MTOR (Affinity Capture-Western), TTI1 (Affinity Capture-Western), TTI1 (Affinity Capture-Western), TELO2 (Affinity Capture-Western), TTI1 (Affinity Capture-MS), TTI1 (Affinity Capture-MS), TTI1 (Affinity Capture-MS), TTI1 (Affinity Capture-MS), TTI1 (Affinity Capture-MS), TTI1 (Affinity Capture-MS), TTI1 (Affinity Capture-MS)

ESM2 similar proteins: A0JMW2, A2VE70, A5WW24, A7E2Y6, B9EJR8, E0CZ22, E1BP36, E7FBU4, O35638, O43156, O70576, O75155, Q08AM6, Q0P5A6, Q0V9L1, Q16401, Q5IFJ8, Q5JTH9, Q5R6L5, Q5ZIW5, Q5ZKD5, Q66L58, Q68F38, Q6DCF2, Q6P5B0, Q6ZQ73, Q7TMY7, Q80W92, Q80WQ2, Q84ZC0, Q86Y56, Q8C0Y0, Q8K2V6, Q8NDA8, Q8WVM7, Q91V83, Q96T76, Q99M76, Q9BPX3, Q9D071

Diamond homologs: O43156, Q91V83

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
CSNK2A1	down-regulates	TTI1	phosphorylation
FBXO9	“down-regulates quantity by destabilization”	TTI1	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	TTI1	polyubiquitination
TTI1	“up-regulates quantity by stabilization”	mTORC1	binding
TTI1	“up-regulates quantity by stabilization”	mTORC2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 148 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.

GO biological processes:

GO term	Partners	Fold	FDR
protein stabilization	10	5.5×	5e-03
G protein-coupled receptor signaling pathway	14	4.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	6
Uncertain significance	191
Likely benign	24
Benign	4

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
2499554	NM_001303457.2(TTI1):c.2998+2T>C	Pathogenic
2573166	NM_001303457.2(TTI1):c.2300T>C (p.Leu767Ser)	Pathogenic
2573167	NM_001303457.2(TTI1):c.2302+1G>T	Pathogenic
2573169	NM_001303457.2(TTI1):c.2978T>G (p.Leu993Arg)	Pathogenic
2499555	NM_001303457.2(TTI1):c.2513C>T (p.Ser838Leu)	Likely pathogenic
2664648	NM_001303457.2(TTI1):c.2990T>C (p.Leu997Pro)	Likely pathogenic
2691770	NM_001303457.2(TTI1):c.1271A>G (p.His424Arg)	Likely pathogenic
3336834	NM_001303457.2(TTI1):c.2011G>A (p.Ala671Thr)	Likely pathogenic
402171	NM_001303457.2(TTI1):c.2761G>A (p.Asp921Asn)	Likely pathogenic
4819591	NM_001303457.2(TTI1):c.106C>T (p.Arg36Ter)	Likely pathogenic

SpliceAI

1879 predictions. Top by Δscore:

Variant	Effect	Δscore
20:37983635:AGACG:A	acceptor_gain	1.0000
20:37983636:GACG:G	acceptor_gain	1.0000
20:37983638:CG:C	acceptor_gain	1.0000
20:37983640:C:CC	acceptor_gain	1.0000
20:37996370:CGTA:C	donor_loss	1.0000
20:37996371:GTA:G	donor_loss	1.0000
20:37996372:TA:T	donor_loss	1.0000
20:37996373:A:AC	donor_gain	1.0000
20:37996373:ACCT:A	donor_gain	1.0000
20:37996374:C:CA	donor_loss	1.0000
20:37996374:C:CC	donor_gain	1.0000
20:37996374:CCT:C	donor_gain	1.0000
20:37996374:CCTC:C	donor_gain	1.0000
20:37996376:T:TA	donor_gain	1.0000
20:37996458:CTCAC:C	acceptor_gain	1.0000
20:37996459:TCAC:T	acceptor_gain	1.0000
20:37996460:CAC:C	acceptor_gain	1.0000
20:37996460:CACC:C	acceptor_gain	1.0000
20:37996461:AC:A	acceptor_gain	1.0000
20:37996461:ACCT:A	acceptor_loss	1.0000
20:37996462:CC:C	acceptor_gain	1.0000
20:37996463:C:CC	acceptor_gain	1.0000
20:37996467:A:T	acceptor_gain	1.0000
20:38000403:A:AC	donor_gain	1.0000
20:38000404:C:CC	donor_gain	1.0000
20:38006192:GTTAC:G	donor_loss	1.0000
20:38006193:TTAC:T	donor_loss	1.0000
20:38006194:TAC:T	donor_loss	1.0000
20:38006195:A:C	donor_loss	1.0000
20:38006196:CCTT:C	donor_gain	1.0000

AlphaMissense

7099 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:38011805:G:T	A671D	0.990
20:37999250:A:G	W911R	0.989
20:37999250:A:T	W911R	0.989
20:38011748:A:G	L690P	0.987
20:38012663:A:G	L385P	0.986
20:38013765:A:G	C18R	0.986
20:38011920:C:G	G633R	0.985
20:38011920:C:T	G633R	0.985
20:38013719:A:G	L33P	0.985
20:38011724:A:G	L698S	0.984
20:38013784:A:C	F11L	0.984
20:38013784:A:T	F11L	0.984
20:38013786:A:G	F11L	0.984
20:38013755:A:G	L21P	0.983
20:37996393:A:G	L1023S	0.982
20:37996918:A:C	F943L	0.981
20:37996918:A:T	F943L	0.981
20:37996920:A:G	F943L	0.981
20:37999248:C:A	W911C	0.981
20:37999248:C:G	W911C	0.981
20:38011847:A:G	L657P	0.980
20:38012684:A:G	L378P	0.980
20:38013655:G:C	F54L	0.980
20:38013655:G:T	F54L	0.980
20:38013657:A:G	F54L	0.980
20:38013650:A:C	L56R	0.977
20:38013674:A:G	L48P	0.977
20:38011806:C:G	A671P	0.976
20:38011839:C:G	A660P	0.976
20:38012522:A:G	L432P	0.976

dbSNP variants (sampled 300 via entrez): RS1000064917 (20:38005482 A>G), RS1000118157 (20:38005260 AC>A), RS1000125159 (20:38009307 T>C), RS1000162354 (20:38003290 T>C), RS1000333857 (20:37991720 T>C), RS1000410484 (20:38009567 G>A), RS1000410715 (20:37992986 A>G), RS1000496267 (20:38004688 G>A), RS1000640298 (20:38031924 G>A), RS1000671620 (20:37992938 G>A), RS1000785090 (20:37998714 C>A), RS1000849320 (20:37997474 G>A), RS1000862063 (20:37986971 A>G), RS1000864643 (20:38018286 T>A), RS1000875784 (20:38029454 T>C)

Disease associations

OMIM: gene MIM:614425 | disease phenotypes: MIM:620445

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with microcephaly and movement abnormalities	Strong	Autosomal recessive
microcephaly	Limited	Autosomal recessive

Mondo (3): neurodevelopmental disorder with microcephaly and movement abnormalities (MONDO:0957531), neurodevelopmental disorder (MONDO:0700092), microcephaly (MONDO:0001149)

Orphanet (0):

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000076	Vesicoureteral reflux
HP:0000252	Microcephaly
HP:0000319	Smooth philtrum
HP:0000369	Low-set ears
HP:0000486	Strabismus
HP:0000565	Esotropia
HP:0000687	Widely spaced teeth
HP:0000742	Self-mutilation
HP:0000749	Paroxysmal bursts of laughter
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000771	Gynecomastia
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001772	Talipes equinovalgus
HP:0002061	Lower limb spasticity
HP:0002066	Gait ataxia
HP:0002072	Chorea
HP:0002216	Premature graying of hair
HP:0002307	Drooling
HP:0002515	Waddling gait
HP:0002650	Scoliosis
HP:0002812	Coxa vara
HP:0002970	Genu varum
HP:0003593	Infantile onset
HP:0004322	Short stature
HP:0007380	Facial telangiectasia

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066412 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.93	Kd	1.175	nM	CHEMBL5653589
8.93	ED50	1.175	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149669: Binding affinity to human TTI1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0012	uM

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects binding, increases reaction, affects cotreatment	4
Cadmium Chloride	decreases expression, increases abundance	2
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
lead acetate	affects cotreatment, decreases expression	1
cobaltous chloride	decreases expression	1
bisphenol S	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Cadmium	decreases expression, increases abundance	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cyclosporine	decreases expression	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
CHEMBL5652711	Binding	Binding affinity to human TTI1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants