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Why is it so difficult to link molecular, cellular, and circuit events with disease phenotype?
Using cortical malformations as an example, @KlinglerEsther @FRANCISFiona7 @silvianeurompi & I discuss this in a review that's just out. Check out thread below https://science.sciencemag.org/content/371/6527/eaba4517
Using cortical malformations as an example, @KlinglerEsther @FRANCISFiona7 @silvianeurompi & I discuss this in a review that's just out. Check out thread below https://science.sciencemag.org/content/371/6527/eaba4517
We start by describing normal cellular events during corticogenesis and highlight what can go wrong. Mutations in tubulin-encoding genes appear to underlie a disproportionate share of cortical malformations, likely reflecting the pleiotropic roles of tubulin across time.
Abnormal developmental cellular processes can result in a variety of macroscopic defects. Microscopic defects, including at the level of the synapse, are probably there too, such that there is likely a continuum between cortical malformations and psychiatric disorders
Somatic mutations also come into play, e.g. in focal cortical dysplasia. We posit that mosaicism might also contribute to neuropsy disorders ( "synaptic mosaicism"?), which has been reported no later than... yesterday by @ChrisAWalsh1's lab, for autism. https://discoveries.childrenshospital.org/mosaic-mutations-autism/
When looking at link between neuronal position & circuit formation in heterotopias, circuit assembly appears quite conserved despite abnormal position. Also, cell-type specific defects in cortical malf. likely exist, but have so far not been examined in detail.
Different processes at play at the genetic, molecular, cellular, circuit, and clinical level interact with one another in different ways to account for disease variability. Stochastic events occur at each of these levels, such that outcome is hard to predict.
Finally, we discuss the importance of stratifying patients using multimodal assessments in order to identify unique disease processes. We also provide new analyses of existing data on spatio-temporal gene expression in select cortical malformation processes.
Also, the article comes with a *free* website, http://www.humous.org/
in which you can compare spatiotemporal gene expression in developing mouse, human embryos, and human brain organoids to compare developmental patterns. Check it out and let us know what you think!
in which you can compare spatiotemporal gene expression in developing mouse, human embryos, and human brain organoids to compare developmental patterns. Check it out and let us know what you think!
Voilà, that's about it but check the original article for full content. If you can't get past the paywall you can DM @KlinglerEsther @silvianeurompi or me. Hope you enjoy the read.
