Gene/phenotype/disorder under study
PRKCE (OMIM 176975)
Abstract
The gene PRKCE (protein kinase C epsilon, PKCε) encodes a serine/threonine kinase belonging to the structurally conserved PKC family that have a variety of functions in different cell types. Despite increasing evidence implicating PKCε in diverse cellular pathways, the consequences of PRKCE disruption in humans remain poorly defined. To date, only a single individual with a de novo p.(Glu599Lys) variant has been reported. That case exhibited clinical features resembling SHORT syndrome, and functional studies demonstrated partial loss of kinase activity, with impaired mTORC2-dependent phospho-priming and reduced activation of AKT.
We have assembled a cohort of more than 15 patients harboring de novo missense variants in PRKCE, where more than half were found to carry the recurrent p.(Glu599Lys) or variants in the p.Gly491/492 hotspot in the PKinase domain. Strikingly, several individuals presented with a shared progeroid phenotype characterized by craniofacial and connective tissue features, along with lipoatrophy, congenital heart anomalies, ocular abnormalities, hearing impairment, and variable neurodevelopmental involvement. Through an array of functional assays, we demonstrate that PRKCE variants impair kinase activation. We aim to expand the mutational and phenotypic spectrum of PRKCE-related developmental disorder adding new patients to this ongoing study.
Contributing clinicians will be acknowledged as co-authors of a future publication.
Coordinating clinicians
Dr. Andrea Accogli – andrea.accogli@mail.mcgill.ca
Dr. Davor Lessel
Institutions
Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada
Institute of Human Genetics, University Regensburg, Regensburg, Germany
Specific requirements beyond clinical data and genotype data sharing:
1- Re-analysis of DNA samples: No
2- Resampling of patients: No
3- Linked to a translational/basic research project: No