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10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
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TTI2
TELO2 interacting protein 2
Chromosome 8 Β· 8p12
NCBI Gene: 80185Ensembl: ENSG00000129696.13HGNC: HGNC:26262UniProt: E5RIH5
34PubMed Papers
21Diseases
0Drugs
8Pathogenic Variants
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
TTT Hsp90 cochaperone complexprotein stabilizationpositive regulation of DNA damage checkpointnucleussevere intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndromeSevere intellectual disability-short stature-behavioral troubles-facial dysmorphism syndromeneurodegenerative diseasegenetic disorder
✦AI Summary

TTI2 (TELO2 interacting protein 2) is an essential component of the conserved Triple T (TTT) complex that serves as a specialized co-chaperone for phosphatidylinositol 3-kinase-related protein kinases (PIKKs) 1. The TTT complex, comprising TELO2, TTI1, and TTI2, modulates the activity, maturation, and stability of critical PIKKs including mTOR, ATM, and ATR by facilitating their proper folding and assembly in cooperation with HSP90 and the R2TP complex 21. Structurally, TTI2 forms an elongated helical repeat structure and binds to the C-terminal end of TTI1 within the TTT complex 3. The complex is essential for DNA damage response pathways and cellular resistance to ionizing radiation, UV, and mitomycin C 3. TTI2 dysfunction has significant disease relevance, as bi-allelic variants cause autosomal recessive intellectual developmental disorder with microcephaly, short stature, and movement disorders 1. Additionally, TTI2 has been implicated as a quantitative trait gene affecting adult hippocampal neurogenesis and glucose metabolism, with heterozygous mutations causing dysglycemia and reduced neurogenesis 4. The protein's role in PIKK stability makes it clinically significant as a potential therapeutic target, with recent evidence suggesting the TTT complex may be targeted by repurposed drugs like ivermectin for cancer therapy 5.

Sources cited
1
TTI2 is part of the TTT complex that modulates PIKK activity and causes neurodevelopmental disorder when mutated
PMID: 36724785
2
TTT complex functions with R2TP and HSP90 as chaperone for PIKK assembly and TOR recruitment
PMID: 34233195
3
Structural details of TTI2 within the TTT complex and its role in DNA damage response
PMID: 34838521
4
TTI2 affects hippocampal neurogenesis and glucose metabolism
PMID: 35377872
5
TTT complex as potential therapeutic target and ivermectin target
PMID: 37175973
Disease Associationsβ“˜21
severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndromeOpen Targets
0.74Strong
Severe intellectual disability-short stature-behavioral troubles-facial dysmorphism syndromeOpen Targets
0.62Moderate
neurodegenerative diseaseOpen Targets
0.53Moderate
genetic disorderOpen Targets
0.47Moderate
autosomal recessive non-syndromic intellectual disabilityOpen Targets
0.46Moderate
lysosomal storage diseaseOpen Targets
0.35Weak
obesityOpen Targets
0.31Weak
Abnormality of the skeletal systemOpen Targets
0.27Weak
microcephalyOpen Targets
0.14Weak
arthritisOpen Targets
0.08Suggestive
neutropenia, severe congenital, 2, autosomal dominantOpen Targets
0.04Suggestive
X-linked severe congenital neutropeniaOpen Targets
0.04Suggestive
ThromboembolismOpen Targets
0.04Suggestive
Blackfan-Diamond anemiaOpen Targets
0.04Suggestive
Recurrent infection due to specific granule deficiencyOpen Targets
0.04Suggestive
nonimmune chronic idiopathic neutropenia of adultsOpen Targets
0.04Suggestive
neutropenia, severe congenital, 1, autosomal dominantOpen Targets
0.03Suggestive
autosomal recessive severe congenital neutropenia due to CSF3R deficiencyOpen Targets
0.03Suggestive
reticular dysgenesisOpen Targets
0.03Suggestive
X-linked sideroblastic anemia 1Open Targets
0.03Suggestive
Intellectual developmental disorder, autosomal recessive 39UniProt
Pathogenic Variants8
NM_001102401.4(TTI2):c.693del (p.Ser230_Trp231insTer)Pathogenic
Inborn genetic diseases
β˜…β˜†β˜†β˜†2025β†’ Residue 230
NM_001102401.4(TTI2):c.1100C>T (p.Pro367Leu)Pathogenic
Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome|Inborn genetic diseases
β˜…β˜†β˜†β˜†2025β†’ Residue 367
NM_001102401.4(TTI2):c.1115+2T>CLikely pathogenic
Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome
β˜…β˜†β˜†β˜†2024
NM_001102401.4(TTI2):c.21_22insAAGCGCTCTG (p.Glu8fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2023β†’ Residue 8
NM_001102401.4(TTI2):c.950A>T (p.Asp317Val)Pathogenic
Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome
β˜†β˜†β˜†β˜†2023β†’ Residue 317
NM_001102401.4(TTI2):c.539T>C (p.Leu180Pro)Pathogenic
Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome
β˜†β˜†β˜†β˜†2023β†’ Residue 180
NM_001102401.4(TTI2):c.575T>C (p.Leu192Pro)Pathogenic
Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome
β˜†β˜†β˜†β˜†2023β†’ Residue 192
NM_001102401.4(TTI2):c.1307T>A (p.Ile436Asn)Pathogenic
Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome
β˜†β˜†β˜†β˜†2013β†’ Residue 436
View on ClinVar β†—
Related Genes
CPN2Shared pathway100%TSPAN1Shared pathway100%ASDURFShared pathway100%PYURFShared pathway100%HAPSTR2Shared pathway100%PAQR4Shared pathway100%
Tissue Expression6 tissues
Brain
100%
Heart
91%
Bone Marrow
57%
Lung
54%
Liver
53%
Ovary
52%
Gene Interaction Network
Click a node to explore
TTI2CPN2TSPAN1ASDURFPYURFHAPSTR2PAQR4
PROTEIN STRUCTURE
Preparing viewer…
PDB7OLE Β· 3.41 Γ… Β· EM
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.76LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.55 [0.40–0.76]
RankingsWhere TTI2 stands among ~20K protein-coding genes
  • #11,266of 20,598
    Most Researched34
  • #3,115of 5,498
    Most Pathogenic Variants8
  • #6,061of 17,882
    Most Constrained (LOEUF)0.76
Genes detectedTTI2
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.
PMID: 36724785
Am J Hum Genet Β· 2023
1.00
2
Systems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose.
PMID: 35377872
PLoS Genet Β· 2022
0.90
3
Structure of the Human TELO2-TTI1-TTI2 Complex.
PMID: 34838521
J Mol Biol Β· 2022
0.80
4
Hippocalcin-Like 1 blunts liver lipid metabolism to suppress tumorigenesis via directly targeting RUVBL1-mTOR signaling.
PMID: 36438486
Theranostics Β· 2022
0.70
5
TTT (Tel2-Tti1-Tti2) Complex, the Co-Chaperone of PIKKs and a Potential Target for Cancer Chemotherapy.
PMID: 37175973
Int J Mol Sci Β· 2023
0.60