PUBLICATION
A Missense Variant in PDK1 Associated with Severe Neurodevelopmental Delay and Epilepsy
- Authors
- Vaz, R., Wincent, J., Elfissi, N., Rosengren Forsblad, K., Pettersson, M., Naess, K., Wedell, A., Wredenberg, A., Lindstrand, A., Ygberg, S.
- ID
- ZDB-PUB-221224-6
- Date
- 2022
- Source
- Biomedicines 10(12): (Journal)
- Registered Authors
- Keywords
- epilepsy, neurodevelopmental delay, pyruvate dehydrogenase kinase, zebrafish
- MeSH Terms
- none
- PubMed
- 36551928 Full text @ Biomedicines
Citation
Vaz, R., Wincent, J., Elfissi, N., Rosengren Forsblad, K., Pettersson, M., Naess, K., Wedell, A., Wredenberg, A., Lindstrand, A., Ygberg, S. (2022) A Missense Variant in PDK1 Associated with Severe Neurodevelopmental Delay and Epilepsy. Biomedicines. 10(12):.
Abstract
The pyruvate dehydrogenase complex (PDC) is responsible for the conversion of pyruvate into acetyl-CoA, which is used for energy conversion in cells. PDC activity is regulated by phosphorylation via kinases and phosphatases (PDK/PDP). Variants in all subunits of the PDC and in PDK3 have been reported, with varying phenotypes including lactic acidosis, neurodevelopmental delay, peripheral neuropathy, or seizures. Here, we report a de novo heterozygous missense variant in PDK1 (c.1139G > A; p.G380D) in a girl with developmental delay and early onset severe epilepsy. To investigate the role of PDK1G380D in energy metabolism and neuronal development, we used a zebrafish model. In zebrafish embryos we show a reduced number of cells with mitochondria with membrane potential, reduced movements, and a delay in neuronal development. Furthermore, we observe a reduction in the phosphorylation of PDH-E1α by PDKG380D, which suggests a disruption in the regulation of PDC activity. Finally, in patient fibroblasts, a mild reduction in the ratio of phosphorylated PDH over total PDH-E1α was detected. In summary, our findings support the notion that this aberrant PDK1 activity is the cause of clinical symptoms in the patient.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping