A Missense Variant in PDK1 Associated with Severe Neurodevelopmental Delay and Epilepsy

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• The pyruvate dehydrogenase complex (PDC) is crucial for cellular energy production.
• PDC activity is tightly regulated by pyruvate dehydrogenase kinases (PDK) and phosphatases.
• Genetic variants in PDC and PDK3 are linked to neurological disorders.

Purpose of the Study:

• To investigate the pathogenicity of a novel de novo heterozygous missense variant in PDK1 (p.G380D).
• To explore the impact of PDK1G380D on cellular energy metabolism and neuronal development.
• To understand the molecular mechanisms underlying clinical symptoms in a patient with this variant.

Main Methods:

• Utilized a zebrafish model to study the functional consequences of PDK1G380D.
• Assessed mitochondrial membrane potential, embryonic movement, and neuronal development in zebrafish.
• Analyzed PDH-E1α phosphorylation in zebrafish and patient-derived fibroblasts.

Main Results:

• Zebrafish embryos with PDK1G380D exhibited reduced mitochondrial activity, impaired movement, and delayed neuronal development.
• The PDK1G380D variant reduced the phosphorylation of PDH-E1α, indicating dysregulated PDC activity.
• Patient fibroblasts showed a mild decrease in the ratio of phosphorylated PDH to total PDH-E1α.

Conclusions:

• The identified de novo heterozygous PDK1 variant (p.G380D) is pathogenic.
• Aberrant PDK1 activity disrupts PDC regulation, leading to impaired energy metabolism and neurodevelopmental deficits.
• This study establishes a link between PDK1 variants and severe early-onset epilepsy and developmental delay.