PRKCE SHORT Manuscript. HMG. Accepted Manuscript.pdf (1017.88 kB)
SHORT syndrome due to a novel de novo mutation in PRKCE (Protein Kinase C?) impairing TORC2-dependent AKT activation
journal contribution
posted on 2023-06-09, 08:03 authored by Diana Alcantara, Frances Elmslie, Martine Tetreault, Eric Bareke, Taila Hartley, Care4Rare Consortium, Jacek Majewski, Kym Boycott, A Micheil Innes, David A Dyment, Mark O'DriscollMark O'DriscollSHORT syndrome is a rare, recognizable syndrome resulting from heterozygous mutations in PIK3R1 encoding a regulatory subunit of phosphoinositide-3-kinase (PI3K). The condition is characterized by short stature, intrauterine growth restriction, lipoatrophy and a facial gestalt involving a triangular face, deep set eyes, low hanging columella and small chin. PIK3R1 mutations in SHORT syndrome result in reduced signaling through the PI3K-AKT-mTOR pathway. We performed whole exome sequencing for an individual with clinical features of SHORT syndrome but negative for PIK3R1 mutation and her parents. A rare de novo variant in PRKCE was identified. The gene encodes PKCe and, as such, the AKT-mTOR pathway function was assessed using phospho-specific antibodies with patient lymphoblasts and following ectopic expression of the mutant in HEK293 cells. Kinase analysis showed that the variant resulted in a partial loss-of-function. Whilst interaction with PDK1 and the mTORC2 complex component SIN1 was preserved in the mutant PKCe, it bound to SIN1 with a higher affinity than wild-type PKCe and the dynamics of mTORC2-dependent priming of mutant PKCe was altered. Further, mutant PKCe caused impaired mTORC2-dependent pAKT-S473 following rapamycin treatment. Reduced pFOXO1-S256 and pS6-S240/244 levels were also observed in the patient LCLs. To date, mutations in PIK3R1 causing impaired PI3K-dependent AKT activation are the only known cause of SHORT syndrome. We identify a SHORT syndrome child with a novel partial loss-of-function defect in PKCe. This variant causes impaired AKT activation via compromised mTORC2 complex function.
History
Publication status
- Published
File Version
- Accepted version
Journal
Human Molecular GeneticsISSN
1460-2083Publisher
Oxford JournalsPublisher URL
External DOI
Issue
19Volume
26Page range
3713-3721Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2017-09-22First Open Access (FOA) Date
2018-07-06First Compliant Deposit (FCD) Date
2017-09-22Usage metrics
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