The unexpected and novel mitochondrial phenotype of the ex vivo patient-derived cellular model for SYNGAP1 encephalopathy.
Biochemical/Metabolic and Therapeutics
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Introduction:
A hallmark of brain metabolism is dynamic coupling between energy demand and supply that involves constant regulation of mitochondrial bioenergetics at prenatal and postnatal stages of brain development. The brain is highly dependent on mitochondrial homeostasis for ATP production via oxidative phosphorylation. SYNGAP1 is caused by sporadic pathogenic nuclear variants in the SYNGAP1 gene, known to play an essential role in brain development and functions, encoding a brain-specific synaptic Ras GTP-ase activating protein localized in dendritic spines of cortical pyramidal neurons. Patients with SYNGAP1 exhibit neurodevelopmental delay, intellectual disability, epileptic encephalopathy, and autism spectrum disorder. The main question addressed in this study is whether the SynGAP1 syndrome could be in part due to a dysregulated mitochondrial energy metabolism
Methods:
To test our hypothesis, we performed skin biopsy and performed comprehensive genetic analysis of the mitochondrial and nuclear genomes by long-range PCR followed by massively parallel sequencing (MitoNGS) and whole exome sequencing (WES) in a patient with SYNGAP1 and mitochondrial features. WES analysis revealed the pathogenic heterozygous nuclear variant c.1783del (p.L595Cfs*55) in the SYNGAP1 gene causing a frameshift located in exon 11. We next used the Brain Gene registry to identify other patients with SYNGAP1 and extrapolated for markers of mitochondrial dysfunction.
Results:
Using the Seahorse technology, we found a significant deficit in spare energy capacity, required for cells to sustain a high energy demand when under stress. The patient’s fibroblasts displayed a defective mitochondrial metabolic plasticity that could not be compensated by glycolysis to overcome the energy deficit.
Conclusion:
In conclusion, our study provides the first evidence of dysregulated mitochondrial energy metabolism associated with the SYNGAP1 syndrome in an ex vivo patient-derived cellular model.
A hallmark of brain metabolism is dynamic coupling between energy demand and supply that involves constant regulation of mitochondrial bioenergetics at prenatal and postnatal stages of brain development. The brain is highly dependent on mitochondrial homeostasis for ATP production via oxidative phosphorylation. SYNGAP1 is caused by sporadic pathogenic nuclear variants in the SYNGAP1 gene, known to play an essential role in brain development and functions, encoding a brain-specific synaptic Ras GTP-ase activating protein localized in dendritic spines of cortical pyramidal neurons. Patients with SYNGAP1 exhibit neurodevelopmental delay, intellectual disability, epileptic encephalopathy, and autism spectrum disorder. The main question addressed in this study is whether the SynGAP1 syndrome could be in part due to a dysregulated mitochondrial energy metabolism
Methods:
To test our hypothesis, we performed skin biopsy and performed comprehensive genetic analysis of the mitochondrial and nuclear genomes by long-range PCR followed by massively parallel sequencing (MitoNGS) and whole exome sequencing (WES) in a patient with SYNGAP1 and mitochondrial features. WES analysis revealed the pathogenic heterozygous nuclear variant c.1783del (p.L595Cfs*55) in the SYNGAP1 gene causing a frameshift located in exon 11. We next used the Brain Gene registry to identify other patients with SYNGAP1 and extrapolated for markers of mitochondrial dysfunction.
Results:
Using the Seahorse technology, we found a significant deficit in spare energy capacity, required for cells to sustain a high energy demand when under stress. The patient’s fibroblasts displayed a defective mitochondrial metabolic plasticity that could not be compensated by glycolysis to overcome the energy deficit.
Conclusion:
In conclusion, our study provides the first evidence of dysregulated mitochondrial energy metabolism associated with the SYNGAP1 syndrome in an ex vivo patient-derived cellular model.