High-throughput screening identifies histone deacetylase inhibitors that modulate GTF2I expression in 7q11.23 microduplication autism spectrum disorder patient-derived cortical neurons.
Francesca Cavallo, Flavia Troglio, Giovanni Fagà and 16 others
PMID 33208191WHAT IT FOUND
A screen did not find compounds that raised target gene expression in Williams syndrome neurons.
In neurons from people with 7q11.23 duplication, three histone deacetylase inhibitors lowered GTF2I levels. Vorinostat was most consistent. Not tested in patients.
Key findings
01Three histone deacetylase inhibitors lowered GTF2I expression in 7Dup patient-derived neurons across four genetically different iPSC lines.
02Vorinostat reduced GTF2I protein levels most consistently across patient-derived lines, while mocetinostat and RG2833 were more variable between mRNA and protein results.
03The primary screen did not confirm any compound able to increase target gene expression more than twofold in WBS neurons.
STILL TO COME
How it was doneWhat they foundWhat it means for SLPs
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What it does not show
The study reports no language, social behavior, cognition, or daily function outcomes. The work is in patient-derived neurons, not in treated patients, so it does not show clinical benefit. The number of cell lines is small, so results may not apply across all people with 7Dup or Williams syndrome. The compounds were tested at 10 μM in cells, and this does not establish safe or effective doses in humans. The mechanism by which histone deacetylase inhibitors lower GTF2I was not tested.
Declared interests
Funding came from the European Research Council, Fondazione Telethon, Consiglio Nazionale delle Ricerche, Regione Lombardia, Fondazione Istituto Europeo di Oncologia-Centro Cardiologico Monzino, and Fondazione Umberto Veronesi. The supplied text does not report a separate author competing-interest declaration.
The easy way to misread this
Do not read the GTF2I lowering in neurons as evidence that vorinostat treats 7Dup or improves language, social, or behavior symptoms. The study measured molecular changes in lab-grown neurons, not patient outcomes.