Authors :
Presenting Author: jie liu, MD – The First Affiliated Hospital of Chongqing Medical University
rui huang, phd – The First Affiliated Hospital of Chongqing Medical University; fenglin tang, phd – The First Affiliated Hospital of Chongqing Medical University; yuanlin ma, phd – The First Affiliated Hospital of Chongqing Medical University; patrick kwan, phd – Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Rationale:
Dishevelled, Egl-10 and Pleckstrin domain-containing 5 (DEPDC5), localized on chromosome 22, 22q12.3, along with Nitrogen permease regulator-like 2 (
NPRL2) and Nitrogen permease regulator-like 3 (
NRPL3), forms the GTPase-activating proteins towards Rags 1 (GATOR1) complex. GATOR1 is an identified inhibitor of the effect of the mammalian or mechanistic target of rapamycin complex 1 (mTORC1).
Identifying the genetic cause of epilepsy may allow a more precision approach to treatm
ent. However, the mechanistic impacts of
DEPDC5 variants are poorly understood, making it difficult to determine their causative role. This is particularly relevant for missense variants, for which it might be challenging to determine the functional consequence.
As a result, the potential functional consequences of most
DEPDC5 variants have been mainly derived from
in silicopredictions and have not been experimentally validated. Here, we report
a DEPDC5 missense variant (c. 2055C >A; p. F685L)
in a three-generation Chinese family with epilepsy affecting nine members, of whom five had died prematurely. We observed co-segregation with phenotype in multiple affected family members.
Methods: To uncover the role and potential biological implications of this missense variant in epilepsy, we created conditional knock-in (CKI) mice using the full-length human wild-type (WT)
DEPDC5 gene (h
DEPDC5WT mice) and the human variant
DEPDC5 gene (
h
DEPDC5F685L mice), respectively. h
DEPDC5 mice were combined with a Nestin promotor-driven Cre allele to stably express D
EPDC5 gene in the central nervous system
Results:
Compared to WT and hDEPDC5WT mice, hDEPDC5F685L animals showed cortical thickening, larger neuron, dyspmorphic neurons, and increased seizure susceptibility. The increase in brain size and neuronal soma size was reversed by rapamycin administration. Rapamycin therapy was shown to lower downstream mTORC1 hyperactivity and reverse the behavioral abnormalities caused by the DEPDC5 variant as well as reduce the mortality in hDEPDC5F685L mice
Conclusions:
Collectively, these results suggest a causative role of the
DEPDC5 (c.C2055A) variant and may account for the epilepsy phenotype and increased mortality observed in the affected individuals.
: This work was supported by grants from the National Natural Science Foundation of China (82271497, 81901322).