23 September 2020
“Samurai” protein mutations cause small, smooth brains
Published online 4 February 2015
Researchers pinpoint three different mutations of a protein that cause abnormalities in the human brain.
Geneticists have identified a protein that plays multiple key roles in brain development and causes severe malformations of the human cerebral cortex when mutated1.
Katanin protein, discovered in 1993, is named after the traditional Japanese sword because it cuts microtubules, the filamentous proteins in the cytoplasm that maintain cell shape and are responsible for cellular movements.
The researchers, led by Wen Hu of Harvard Medical School, studied seven members of three unrelated Middle Eastern families — one Jordanian, another Saudi Arabian, and the third Palestinian – with severe microlissencephaly, or an abnormally small and smooth brain.
All seven affected individuals carried one of three different mutations in the KATNB1 gene, which encodes regulatory subunit p80 of the Katanin protein, resulting in lower Katanin levels.
“We are now trying to figure out what is the most important function for the control of the size of the brain."
Using genetic engineering to create mouse and zebrafish embryos missing the KATNB1 gene, the research shows that embryos lacking both copies showed various brain abnormalities, had dramatically reduced body size, and died before birth. This indicates that Katanin p80 is needed for proper development and survival of the embryo.
KATNB1 is expressed throughout the embryonic brain and is enriched in the developing neocortex. Embryos missing the gene have much fewer proliferating neuronal progenitors and in turn a marked reduction in cortical thickness.
Cells lacking the gene have abnormally shaped mitotic spindles, to which the protein is localized and that segregate the chromosomes during cell division, affecting their ability to divide. They also have too many cilia, the hair-like structures that protrude from the surface of all cells and play important roles in cell division and developmental signaling.
“We are now trying to figure out what is the most important function for the control of the size of the brain — is it the role of these genes in control of the mitotic spindle? Or is it their role in the control of the cilia, which controls the response of cells to growth factors and other factors that regulate cell division?” comments senior author Christopher Walsh.
- Hu, W. F. et al. Katanin p80 regulates human cortical development by limiting centriole and cilia number. Neuron (2014). http://dx.doi.org/10.1016/j.neuron.2014.12.017