MED13L and its disease-associated variants influence the dendritic development of cerebral cortical neurons in the mammalian brain

Summary

(Nanako Hamada and Koh-ichi Nagata)

Using embryonic mouse neurons, Hamada and colleagues showed disparity amongst missense (p.Pro866Leu, p.Ser2163Leu, p.Ser2177Tyr, p.Thr2162Met) and nonsense (p.Gln1922) variants.
Some variants accumulated inthe nucleus while others were in the cytoplasm, the outside of the cell.
The nonsense variant was hardly detectable aligning with haploinsufficiency with some impairment on dendrite (nerve cell responsible for excitatory function) development.
The variant p.Pro866Leu missense variant showed a reduced number and length of dendrites (nerve cell) in a dominant-negative manner (i.e. not haploinsufficient)
The p.Ser2163Leu variant impaired both dendrite and synaptic formation, but in opposite manners, exhibiting both a loss and a gain of function, respectively.
Finally, p.Thr2162Met variant had a reduced function, not quite a total loss as seen in the nonsense variant
Clinical symptoms collected showed that individuals that had variants with gains-of-function also had seizures, autism, and low tone, showing that the variants’ interaction on nerve cell development led to more pronounced clinical symptoms.
This newest scientific study provides knowledge that different variants at different points along MED13L protein may have different functions, showing that multiple treatment choices my be necessary.