TY - JOUR
T1 - iPSC-derived neurons of CREBBP- and EP300-mutated Rubinstein-Taybi syndrome patients show morphological alterations and hypoexcitability
AU - Alari, Valentina
AU - Russo, Silvia
AU - Terragni, Benedetta
AU - Ajmone, Paola Francesca
AU - Sironi, Alessandra
AU - Catusi, Ilaria
AU - Calzari, Luciano
AU - Concolino, Daniela
AU - Marotta, Rosa
AU - Milani, Donatella
AU - Giardino, Daniela
AU - Mantegazza, Massimo
AU - Gervasini, Cristina
AU - Finelli, Palma
AU - Larizza, Lidia
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder characterized by distinctive facial features, growth retardation, broad thumbs and toes and mild to severe intellectual disability, caused by heterozygous mutations in either CREBBP or EP300 genes, encoding the homologous CBP and p300 lysine-acetyltransferases and transcriptional coactivators. No RSTS in vitro induced Pluripotent Stem Cell (iPSC)-neuronal model is available yet to achieve mechanistic insights on cognitive impairment of RSTS patients. We established iPSC-derived neurons (i-neurons) from peripheral blood cells of three CREBBP- and two EP300-mutated patients displaying different levels of intellectual disability, and four unaffected controls. Pan neuronal and cortical-specific markers were expressed by all patients’ i-neurons. Altered morphology of patients’ differentiating neurons, showing reduced branch length and increased branch number, and hypoexcitability of differentiated neurons emerged as potential disease biomarkers. Anomalous neuronal morphology and reduced excitability varied across different RSTS patients’ i-neurons. Further studies are needed to validate these markers and assess whether they reflect cognitive and behavioural impairment of the donor patients.
AB - Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder characterized by distinctive facial features, growth retardation, broad thumbs and toes and mild to severe intellectual disability, caused by heterozygous mutations in either CREBBP or EP300 genes, encoding the homologous CBP and p300 lysine-acetyltransferases and transcriptional coactivators. No RSTS in vitro induced Pluripotent Stem Cell (iPSC)-neuronal model is available yet to achieve mechanistic insights on cognitive impairment of RSTS patients. We established iPSC-derived neurons (i-neurons) from peripheral blood cells of three CREBBP- and two EP300-mutated patients displaying different levels of intellectual disability, and four unaffected controls. Pan neuronal and cortical-specific markers were expressed by all patients’ i-neurons. Altered morphology of patients’ differentiating neurons, showing reduced branch length and increased branch number, and hypoexcitability of differentiated neurons emerged as potential disease biomarkers. Anomalous neuronal morphology and reduced excitability varied across different RSTS patients’ i-neurons. Further studies are needed to validate these markers and assess whether they reflect cognitive and behavioural impairment of the donor patients.
KW - Cognitive impairment
KW - Disease-relevant cell phenotypes
KW - iPSCs
KW - Neuronal model
KW - Rubinstein-Taybi syndrome
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U2 - 10.1016/j.scr.2018.05.019
DO - 10.1016/j.scr.2018.05.019
M3 - Article
AN - SCOPUS:85048473649
VL - 30
SP - 130
EP - 140
JO - Stem Cell Research
JF - Stem Cell Research
SN - 1873-5061
ER -