Table 1.
Summary of selected signalopathy-associated clinical phenotypes and respective findings in rodent and human cell models.
| Clinical Phenotypes (Frequency) |
Animal Models | Human Cell Models | Mutations in 10,000 ASD Cases [19] | |
|---|---|---|---|---|
| mTOR Pathway | ||||
| TSC1-2 |
Tuberous Sclerosis (1:10,000) ASD, ID, epilepsy, structural neurological changes, cancers/tumors, skin problems |
Altered synaptic plasticity; altered social behavior; altered learning behavior and memory; disrupted neuronal cell development; seizures | Increased dendritic branching; altered synaptic plasticity; enlarged cell size |
TSC1: n.d. TSC2: 3.8 |
| PTEN |
Cowden Syndrome (1:250,000) ASD, ID, epilepsy, structural neurological changes, cancers/tumors, skin problems |
Altered synaptic plasticity; altered social behavior; altered learning behavior and memory; disrupted neuronal cell development; seizures | Impaired cortical folding | PTEN: 4.4 |
| AKT1-3 |
Cowden Syndrome (1–9:1,000,000) and AKT1-related Proteus Syndrome ASD, ID, epilepsy, structural neurological changes, cancers/tumors |
Altered synaptic plasticity; altered social behavior; altered learning behavior and memory; disrupted neuronal cell development; seizures | Increased dendritic branching; altered synaptic plasticity; enlarged cell size |
AKT1: n.d. AKT2: 1.3 AKT3: 1.3 |
| MTOR | ASD, ID, epilepsy, structural neurological changes, cancers/tumors | Disrupted neuronal cell development; seizures | MTOR: 0.6 | |
| RICTOR/RAPTOR | ASD, ID, epilepsy, structural neurological changes, cancers/tumors | Altered synaptic plasticity; disrupted neuronal cell development | RICTOR: n.d. RAPTOR: 2.5 | |
| RHEB | ASD, ID, epilepsy, structural neurological changes, cancers/tumors | Altered synaptic plasticity; disrupted neuronal cell development; seizures | n.d. | |
| S6K | ASD, ID, epilepsy, structural neurological changes, cancers/tumors, skin problems | Minor altered synaptic plasticity; altered learning behavior and memory; altered social behavior; disrupted neuronal cell development | RPS6KB1: 1.9 | |
| eIF4EeIF4E-B | ASD, ID, epilepsy, structural neurological changes, cancers/tumors | Altered synaptic plasticity; altered social behavior; altered learning behavior and memory; disrupted neuronal cell development | EIF4B: 0.6 | |
| DEPDC5 | ASD, ID, epilepsy, structural neurological changes, cancers/tumors | Altered synaptic plasticity; disrupted neuronal cell development; seizures | Enlarged cell size; increased proliferation rates | DEPDC5: 0.6 |
| NPRL2 | ASD, ID, epilepsy, structural neurological changes, cancers/tumors | n.d | ||
| RAS Pathway | ||||
| SYNGAP1 |
SYNGAP1-ID ASD, ID, epilepsy, schizophrenia |
Altered synaptic plasticity (reduced hippocampal LTP and early spine maturation); elevated protein synthesis; altered spatial learning and memory, social novelty, fear memory and increased locomotor activity | SYNGAP1: 10.8 | |
| NF1 | NF1 Syndrome (1: 3000): ASD, ID, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors, skin problems | Altered synaptic plasticity (reduced hippocampal LTP and spine density); altered spatial learning and memory, social learning, attention and working memory deficits | Altered proliferation, apoptosis and neuronal differentiation | NF1: 4.4 |
| SPRED1 |
Legius Syndrome ASD, ID, structural neurological changes., congenital heart disease, skin problems |
Altered synaptic plasticity (reduced hippocampal LTP), altered spatial learning and memory and social behavior | SPRED1: 0.6 | |
| SOS1 |
Noonan Syndrome (1:2000) ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors |
craniofacial abnormalities; cardiac defects | n.d. | |
| CBL |
Noonan Syndrome (1:2000) ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors |
CBL: 0.6 | ||
| HRAS |
Costello Syndrome (1:300,000–1.25 mil.) ASD, ID, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors, skin problems |
Increased soma size and spine complexity: enhanced LTP; altered spatial learning and memory and contextual fear conditioning | Increased astrogenesis, increased proteoglycans, dysregulated cortical maturation | n.d. |
| NRAS |
Noonan Syndrome (1:2000) ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors |
Leukemias, craniofacial abnormalities, cardiac defects | n.d. | |
| KRAS |
CFC and Noonan Syndrome ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors |
Altered synaptic plasticity (reduced hippocampal LTP); elevated protein synthesis; altered spatial learning and memory, working memory; normal social behaviors | KRAS: 0.6 | |
| RIT1 |
Noonan Syndrome (1:2000) ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors |
Reduced dendritic length and complexity | n.d. | |
| RAF1 |
Noonan Syndrome (1:2000) ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors |
Increased astroglial cell density; enhanced spatial learning and memory | n.d. | |
| BRAF |
CFC and Noonan Syndrome ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors |
Altered synaptic plasticity (reduced hippocampal LTP); altered spatial learning and memory; seizures | Inhibited neuronal differentiation; premature differentiation and impaired cortical layering | BRAF: 1.3 |
| MEK1/2 |
CFC Syndrome (1:800,000) ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors |
Increased astroglial cells, neuronal loss; altered spatial learning and memory; altered fear conditioning; craniofacial abnormalities | MAP2K1: 0.6MAP2K2: 1.3 | |
| PTPN11 (SHP2) |
Noonan Syndrome (1:2000) ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors |
Altered synaptic plasticity; altered spatial learning and memory; increased hyperactivity, reduced anxiety behavior | Inhibited differentiation, increased gliogenesis; reduced neurite outgrowth; lower spontaneous firing rate | PTPN11: 1.3 |
| LZTR1 | Noonan Syndrome (1:2000) | LZTR1: 3.2 | ||
Abbreviations: ASD Autism Spectrum Disorder, ID Intellectual Disability, LTP Long Term Potentiation; n.d. not detected. The central disorders are in bold.