A Missense Variant in PDK1 Associates with Severe Developmental Delay and Epilepsy
Abstract number :
1.208
Submission category :
4. Clinical Epilepsy / 4B. Clinical Diagnosis
Year :
2022
Submission ID :
2204263
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Sofia Ygberg, PhD – Karolinska Hospital; Raquel Vaz, - – KI; Josephine Wincent, Dr – KI; Najla Elfissi, Dr – MBB/KI; Kristina Forsblad, Dr – Akademiska Hospital; maria Pettersson, Dr – KI; Karin Naess, Dr – KI; anna wedell, Prof – KI; Anna Wredenberg, Dr – KI; Anna Lindstrand, Prof – KI
Rationale: The pyruvate dehydrogenase complex (PDC), located in the mitochondrial matrix, is responsible for the conversion of pyruvate into acetyl-CoA, used for energy production in cells. PDC activity is tightly regulated by phosphorylation, via kinases and phosphatases (PDK/PDP), that respond to, for example, the amount of substrate in the cell (e.g., pyruvate or NADH) and hypoxia. Mutations in all subunits of the PDC and in PDK3 have been reported and the clinical presentation often includes lactic acidosis, neurodevelopmental delay, and seizures. Here we report a missense mutation in PDK1, a gene not previously associated with human disease.
Methods: Genetic analysis with trio whole genome sequencing and Zebrafish model.
Results: Genetic analysis using trio genome sequencing identified a de novo missense variant in PDK1 (c.1139G >A, in a patient with developmental delay and early onset severe epilepsy p.Gly380Asp). Functional studies in zebrafish were performed by overexpressing human wild type and mutant PDK1 in early-stage embryos with reduced endogenous PDK1. In zebrafish, mutant PDK1 failed to phosphorylate PDHE1 (pyruvate dehydrogenase) resulting in abnormal mitochondrial function. This, in turn, affected muscle activity, seen by reduced bout movement in fish expressing mutant PDK1 when compared to control embryos, as well as abnormal neuronal development.
Conclusions: We present PDK1 as a novel disease-causing candidate gene. Current treatment of PDC deficiency is ketogenic diet, which also had a positive effect in the described child. Nevertheless, further knowledge on PDK1 function in relation to PDC may aid the development of novel therapies specifically targeting PDC associated diseases.
Funding:
Clinical Epilepsy