Table 1.
Examples of neurodevelopmental diseases that have been modeling using human iPSC
| Disease | Incidence | Age of neuropathological onset |
Key gene (chromosome) |
Genetic mutation in fibroblasts used for reprogramming |
Reprogramming method |
Neuronal differentiation and validation |
Relevant neuronal phenotype |
Candidate drug |
Reference |
|---|---|---|---|---|---|---|---|---|---|
| RTT | 1:10,000 (female) [22] | ½–1½ years old [22] | MeCP2 (X) | Nonsense (Q244X) Missense (T158M, R306C) | Retrovirus (4 factors) | Yes; TuJ1+, MAP2+, GABA+, Synapsin+, VGLUT1+ Electrophysiologically active | Reduced soma size, dendritic spine density and synapses Altered Ca2+ signaling electrophysiological defect | IGF1 | Marchetto [11••] |
| Null (Δexon3–4) Missense (T158M, R306C) | Retrovirus (4 factors) | Yes; MAP2+ | Reduced soma size | No | Cheung [12] | ||||
| Nonsense (Q244X) Missense (T158M, R306C) | Retrovirus (4 factors) | Yes; TuJ1+, SCN1A/B+ | Lower expression of mature neuron markers | No | Kim [15] | ||||
| Nonsense (V247X, R294X) Missense (T158M, R306C) | Retrovirus and Lentivirus (4 factors) | Yes; TuJ1+ | Reduced nuclear size | No | Ananiev [13] | ||||
| FXS | 1:4000–1:6000 [36] | <3 years old [36] | FMR1 (X) | >200 CGG repeats in 5′UTR | Retrovirus (4 factors) | No | No | No | Urbach [37••] |
| >700 CGG repeats in 5′UTR | Retrovirus (4 factors) | Yes; TuJ1+ | Fewer and shorter neurites | No | Sheridan [17] | ||||
| SCZD | 1:100 [38] | Typically 15–25 years old In rare case, <10 years old [39] | DISC1 (1) | Δexon-intron12 region (4bp) | Integration-free episomes (4 factors) | No | No | No | Chiang [40] |
| Sporadic | Unknown | Tetracyclin-inducible lentivirus (5 factors) | Yes; TuJ1+, MAP2+, PSD95+, VGLUT1+, GAD65/67+ Electrophysiologically active | Reduced neuronal connectivity and neurite number, decreased PSD-95 expression | Loxapine | Brennand [16•] | |||
| TS | Unknown (20 cases reported worldwide [41]) | >2.5 years old [41,42] | CACNA1C (12) | Missense (G406R) | Retrovirus (4 factors) | Yes; MAP2+, VGLUT1/2+, TH+, GAD65/67+, CTIP2+, FOXP1+, SATB2+, Electrophysiologically active | Defect in Ca2+ signaling and electrophysiology, decreased SATB2 expression §Higher expression of TH and catecholamines | Roscovitine | Pasca [18••] |
| CDKL5-related disorder | Unknown (80 cases reported worldwide [43]) | 2–3 months old [44] | CDKL5 (X) | Nonsense (Q347X) Missense (T288I) | Retrovirus (4 factors) | Yes; TuJ1+, MAP2+, VGLUT1/2+, GAD65/67+ | No | No | Amenduni [19] |
| AS | 1:12,000 [45] | 2–3 years old [46] | Maternal UBE3A (15) | Maternal Δ15q11-q13 (including UBE3A) | Retrovirus (5 factors) | Yes; TuJ1+, MAP2+, SynapsinI+, PanNav+ Electrophysiologically active | No | No | Chamberlain [20] |
| PWS | 1:15,000 [47] | 2–6 years old [48] | Unknown in paternal | Paternal Δ15q11-q13 | Retrovirus (5 factors) | No | No | No | Chamberlain [20] |
| 15q11-q13 (15) | t(15;4)(q11.2;q27) | Retrovirus (4 factors) | Yes; TuJ1+, MAP2+ | No | No | Yang [21] |
4 factors, OCT4, SOX2, KLF4 and c-MYC; 5 factors, OCT4, SOX2, KLF4, c-MYC and LIN28;
§
not observed in animal.