Abstract
AbstractPathogenicACTBandACTG1gene variants, encoding the actin isoformsβCYA andγCYA, respectively, are frequently associated with theBaraitser-Winter-CerebroFrontoFacial syndrome (BWCFF-S) that includes malformations of cortical development. Here we explore whether cerebral organoids grown from BWCFF-S patient-derived induced pluripotent stem cells can provide insight into the pathogenesis underlying the cortical malformations of these patients. Cerebral organoids expressing either anACTBor anACTG1gene variant, each with a point mutation resulting in a single amino acid substitution, are reduced in size, showing smaller ventricle-like structures with a thinner ventricular zone (VZ). This decrease in VZ- progenitors is associated with a striking change in the orientation of their cleavage plane from predominantly vertical (control) to predominantly horizontal (BWCFF-S), which is incompatible with increasing VZ-progenitor abundance. The underlying cause appears to be an altered subcellular tubulin localization due to the actin mutations that affects mitotic spindle positioning of VZ-progenitors in BWCFF-S.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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1. Genetics of human brain development;Nature Reviews Genetics;2023-07-28