TRIO — trio Rho guanine nucleotide exchange factor

14 sources retrieved · Most recent: April 2026 · Index updated 20 days ago

131PubMed Papers

#3,560 · top 18% of 19K genes

22Diseases

top 5%

0Drugs

175Pathogenic Variants

top 8%

OMIM Disease GeneHighly ConstrainedKinaseVariant-RichExperimental GO EvidenceSwiss-Prot Reviewed

postsynaptic modulation of chemical synaptic transmissioncytosolprotein bindingneuron projection morphogenesisintellectual developmental disorder, autosomal dominant 63, with macrocephalymicrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndromegenetic disorderIntellectual disability

AI Summary

TRIO is a Rho guanine nucleotide exchange factor (GEF) that activates the GTPases RAC1 and RHOA to coordinate actin remodeling essential for cell migration and growth 1. In neurons, TRIO plays a critical role in regulating neurite outgrowth, lamellipodia formation, and axon guidance 1. During hippocampal development, TRIO limits dendrite formation and subsequently regulates synaptic function through AMPAR endocytosis at excitatory synapses. TRIO also transcriptionally regulated by YAP to promote cell migration and invasion in physiological and cancer contexts by modulating the RAC1-RhoA GTPase switch 2. Pathogenic TRIO variants cause neurodevelopmental disorders with domain-specific effects 1. Variants in the seventh spectrin repeat cause RAC1 hyper-activation, resulting in severe intellectual disability with macrocephaly, while GEFD1 domain variants cause RAC1 hypo-activation, associated with milder intellectual disability and microcephaly 1. Comprehensive analysis of 25 additional TRIO variant carriers reveals developmental delay, learning difficulties, seizures, behavioral abnormalities, and previously unreported structural brain malformations including corpus callosum and ventricular abnormalities 3. This tight control of TRIO-RAC1 signaling is essential for normal neuronal development, with dysregulation contributing to intellectual developmental disorders and autism spectrum disorders.

Sources cited

TRIO is a RhoGEF that activates RAC1 to regulate neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis; domain-specific variants cause opposite RAC1 modulation correlated with macrocephaly vs. microcephaly phenotypes

PMID: 32109419

YAP transcriptionally activates TRIO to promote cell migration and invasion through RAC1 activation and RhoA inhibition; hyperactivation of YAP-TRIO signaling associated with poor survival in glioblastoma

PMID: 40424361

25 patients with TRIO variants show developmental delay, learning difficulties, seizures, behavioral issues, and structural brain abnormalities including corpus callosum and ventricular abnormalities; strengthens genotype-to-phenotype correlation

PMID: 36987741

⚠Limited data available — This gene has 3 indexed publications. Summary and analysis may be incomplete.

Disease Associations22

intellectual developmental disorder, autosomal dominant 63, with macrocephalyOpen Targets

0.77Strong

micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndromeOpen Targets

0.76Strong

genetic disorderOpen Targets

0.55Moderate

Intellectual disabilityOpen Targets

0.52Moderate

syndromic intellectual disabilityOpen Targets

0.45Moderate

neurodegenerative diseaseOpen Targets

0.42Moderate

developmental disabilityOpen Targets

0.36Weak

hearing loss, autosomal recessiveOpen Targets

0.35Weak

Tip-toe gaitOpen Targets

0.34Weak

idiopathic pulmonary fibrosisOpen Targets

0.32Weak

HypercholesterolemiaOpen Targets

0.32Weak

cholelithiasisOpen Targets

0.29Weak

retinal degenerationOpen Targets

0.28Weak

Neurodevelopmental delayOpen Targets

0.28Weak

cardiovascular diseaseOpen Targets

0.27Weak

deafnessOpen Targets

0.27Weak

microcephalyOpen Targets

0.27Weak

asthmaOpen Targets

0.26Weak

heart conduction diseaseOpen Targets

0.21Weak

alcohol drinkingOpen Targets

0.20Weak

Intellectual developmental disorder, autosomal dominant 44, with microcephalyUniProt

Intellectual developmental disorder, autosomal dominant 63, with macrocephalyUniProt

Pathogenic Variants175

NM_007118.4(TRIO):c.5497-1G>CLikely pathogenic

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome;Intellectual developmental disorder, autosomal dominant 63, with macrocephaly|Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome

★★☆☆2026

NM_007118.4(TRIO):c.7050del (p.Val2351fs)Pathogenic

Intellectual developmental disorder, autosomal dominant 63, with macrocephaly|not provided|Inborn genetic diseases|Autosomal dominant TRIO-related disorders

★★☆☆2025→ Residue 2351

NM_007118.4(TRIO):c.4231C>T (p.Arg1411Ter)Pathogenic

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome|Inborn genetic diseases

★★☆☆2025→ Residue 1411

NM_007118.4(TRIO):c.4513C>T (p.Arg1505Ter)Pathogenic

not provided|Autosomal dominant TRIO-related disorders

★★☆☆2025→ Residue 1505

NM_007118.4(TRIO):c.4283G>A (p.Arg1428Gln)Pathogenic

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome|not provided|TRIO-related disorder

★★☆☆2025→ Residue 1428

NM_007118.4(TRIO):c.7217_7218del (p.Ala2406fs)Pathogenic

not provided|Inborn genetic diseases

★★☆☆2025→ Residue 2406

NM_007118.4(TRIO):c.6153+1G>APathogenic

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome|Inborn genetic diseases|not provided

★★☆☆2025

NM_007118.4(TRIO):c.838C>T (p.Gln280Ter)Pathogenic

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome|not provided

★★☆☆2025→ Residue 280

NM_007118.4(TRIO):c.4394A>G (p.Asn1465Ser)Pathogenic

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome|not provided|Intellectual developmental disorder, autosomal dominant 63, with macrocephaly|TRIO-related disorder|Intellectual developmental disorder, autosomal dominant 63, with macrocephaly;Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome

★★☆☆2025→ Residue 1465

NM_007118.4(TRIO):c.3232C>T (p.Arg1078Trp)Pathogenic

not provided|Inborn genetic diseases|Autosomal recessive nonsyndromic hearing loss 28|Intellectual developmental disorder, autosomal dominant 63, with macrocephaly|Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome|Intellectual disability|Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome;Intellectual developmental disorder, autosomal dominant 63, with macrocephaly

★★☆☆2025→ Residue 1078

NM_007118.4(TRIO):c.3447+2T>CLikely pathogenic

TRIO-related disorder|not provided

★★☆☆2023

NM_007118.4(TRIO):c.4292A>T (p.Lys1431Met)Pathogenic

Inborn genetic diseases|TRIO-related disorder

★★☆☆2023→ Residue 1431

NM_007118.4(TRIO):c.3233G>A (p.Arg1078Gln)Pathogenic

Intellectual developmental disorder, autosomal dominant 63, with macrocephaly|not provided|Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome|Inborn genetic diseases|TRIO-related disorder

★★☆☆2023→ Residue 1078

NM_007118.4(TRIO):c.4382C>G (p.Pro1461Arg)Pathogenic

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome

★★☆☆2023→ Residue 1461

NM_007118.4(TRIO):c.3657dup (p.Cys1220fs)Pathogenic

not provided|Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome

★★☆☆2022→ Residue 1220

NM_007118.4(TRIO):c.4300C>T (p.Leu1434Phe)Likely pathogenic

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome|not provided

★★☆☆2022→ Residue 1434

NM_007118.4(TRIO):c.6092dup (p.Leu2031fs)Pathogenic

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome|Intellectual disability|not provided|See cases

★★☆☆2022→ Residue 2031

NM_007118.4(TRIO):c.4387C>T (p.Arg1463Ter)Pathogenic

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome|Intellectual developmental disorder, autosomal dominant 63, with macrocephaly

★★☆☆2021→ Residue 1463

NM_007118.4(TRIO):c.4282C>T (p.Arg1428Ter)Pathogenic

not provided

★★☆☆2021→ Residue 1428

NM_007118.4(TRIO):c.651_652del (p.Arg217fs)Pathogenic

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome|not provided

★★☆☆2020→ Residue 217

Tissue Expression6 tissues

Ovary

100%

Brain

75%

Lung

66%

Heart

60%

Liver

42%

Bone Marrow

38%

Gene Interaction Network6 neighbors

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Structure4 PDB hits

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PDB1NTY · 1.70 Å · X-ray

View on RCSB

ConstraintgnomAD v4.1

LOEUFⓘ

0.22Highly Constrained

pLIⓘ

1.00Intolerant

Observed/Expected LoF0.17 [0.14–0.22]

Rankings3 dim

Where TRIO stands among ~20K protein-coding genes

#3,578of 20,598
Most Researched131 · top quartile
#417of 5,498
Most Pathogenic Variants175 · top 10%
#550of 17,882
Most Constrained (LOEUF)0.22 · top 5%