Thread by @biomilly

Excited to share with you all the latest paper from @LabMirzaa : an intriguing (I might be biased) story on inverse brains growth phenotypes due to mutations in proximal vs distal regions of CCND2. #research #neuroscience #raredisorders onlinelibrary.wiley.com/doi/10.1002/aj…

We found that frameshift and nonsense variants in the proximal domain of CCND2 lead to microcephaly, short stature and mild intellectual impairment in three unrelated families.

Previous findings from our lab and other had associated missense variants in the distal region of CCND2 to MPPH, a complex phenotype with megalencephaly.

We used cell lines from patients with a proximal variant (potential loss of function) and one distal variant (potential gain of function) to investigate cellular phenotypes and potential mechanisms.

We found that the mutant cell line with proximal variant was still able to produce the protein and had a slight increase of pS6, a marker of hyperactivstion of MTOR pathway.

The mutant cell line with the distal variant presented a significant increase in pS6 and other components of the MTOR pathway, had increased proliferation (confirming our previous data in mouse and HEK cells) and hypertrophy (new finding)

We speculate that both variants might lead to accumulation of unphosphorilated, degradation resistant CCND2 in the cells, however leading to two different phenotypes due to the loss of function/gain of function variants

Further experiments in more relevant models (organoids and CCND2 mouse models) are needed to better understand the pathomechanism, although these findings have expanded the spectrum of CCND2 -related disorders, and will be helpful for patiants’ diagnosis and prognosis.

A huge thanks to the families, the collaborators and the amazing @ghaydamirzaa that made this possible. Also, a reminder to use @GeneMatcher and similar tools, collaboration is the power of science!