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SHORT syndrome due to a novel de novo mutation in PRKCE (Protein Kinase Cɛ) impairing TORC2-dependent AKT activation.

Alcantara, D; Elmslie, F; Tetreault, M; Bareke, E; Hartley, T; Care4Rare Consortium, ; Majewski, J; Boycott, K; Innes, AM; Dyment, DA; et al. Alcantara, D; Elmslie, F; Tetreault, M; Bareke, E; Hartley, T; Care4Rare Consortium; Majewski, J; Boycott, K; Innes, AM; Dyment, DA; O'Driscoll, M (2017) SHORT syndrome due to a novel de novo mutation in PRKCE (Protein Kinase Cɛ) impairing TORC2-dependent AKT activation. Hum Mol Genet, 26 (19). pp. 3713-3721. ISSN 1460-2083 https://doi.org/10.1093/hmg/ddx256
SGUL Authors: Elmslie, Frances

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Abstract

SHORT 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 PKCε 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 PKCε, it bound to SIN1 with a higher affinity than wild-type PKCε and the dynamics of mTORC2-dependent priming of mutant PKCε was altered. Further, mutant PKCε 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 PKCε. This variant causes impaired AKT activation via compromised mTORC2 complex function.

Item Type: Article
Additional Information: This is a pre-copyedited, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Diana Alcantara, Frances Elmslie, Martine Tetreault, Eric Bareke, Taila Hartley, Care4Rare Consortium, Jacek Majewski, Kym Boycott, A. Micheil Innes, David A. Dyment, Mark O’Driscoll, SHORT syndrome due to a novel de novo mutation in PRKCE (Protein Kinase Cɛ) impairing TORC2-dependent AKT activation, Human Molecular Genetics, Volume 26, Issue 19, 01 October 2017, Pages 3713–3721 is available online at: https://doi.org/10.1093/hmg/ddx256
Keywords: Adaptor Proteins, Signal Transducing, Adolescent, Dwarfism, Female, Growth Disorders, HEK293 Cells, Humans, Hypercalcemia, Mechanistic Target of Rapamycin Complex 2, Metabolic Diseases, Mutation, Nephrocalcinosis, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Kinase C-epsilon, Proto-Oncogene Proteins c-akt, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Care4Rare Consortium, Humans, Dwarfism, Nephrocalcinosis, Metabolic Diseases, Hypercalcemia, Growth Disorders, Sirolimus, Adaptor Proteins, Signal Transducing, Signal Transduction, Phosphorylation, Mutation, Adolescent, Female, Proto-Oncogene Proteins c-akt, Protein Kinase C-epsilon, Phosphatidylinositol 3-Kinases, HEK293 Cells, TOR Serine-Threonine Kinases, Mechanistic Target of Rapamycin Complex 2, Adaptor Proteins, Signal Transducing, Adolescent, Dwarfism, Female, Growth Disorders, HEK293 Cells, Humans, Hypercalcemia, Mechanistic Target of Rapamycin Complex 2, Metabolic Diseases, Mutation, Nephrocalcinosis, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Kinase C-epsilon, Proto-Oncogene Proteins c-akt, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, 06 Biological Sciences, 11 Medical And Health Sciences, Genetics & Heredity
Journal or Publication Title: Hum Mol Genet
ISSN: 1460-2083
Language: eng
Dates:
DateEvent
1 October 2017Published
6 July 2017Published Online
29 June 2017Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
C24110/A15394Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
UNSPECIFIEDCanadian Institutes of Health Researchhttp://dx.doi.org/10.13039/501100000024
PubMed ID: 28934384
Web of Science ID: WOS:000411069400005
Go to PubMed abstract
URI: http://sgultest.da.ulcc.ac.uk/id/eprint/110996
Publisher's version: https://doi.org/10.1093/hmg/ddx256

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