Unusually High Number of Mitochondrial DNA Seen in Patients
The copy number of mitochondrial DNA (mtDNA) is increased significantly in patients with Rett syndrome, possibly indicating mitochondrial dysfunction, a study reported.
Researchers suggest that this increase in the copy number of mtDNA is an attempt to compensate for decreased energy availability. Mitochondria are the producers of energy within a cell.
The team believes that mtDNA could potentially be a predictive marker for neurodevelopmental diseases like Rett.
The study, “Mitochondrial DNA Copy Number in Rett Syndrome Caused by Methyl-CpG-Binding Protein-2 Variants,” was published in The Journal of Pediatrics.
The MECP2 gene is mutated in Rett syndrome. The gene itself codes for the MeCP2 protein, which is involved in the activation and repression of transcription — the process by which DNA is copied into RNA to be used as a template for protein production. The MeCP2 protein thus can control which genes are “turned on” or “turned off.”
MeCP2 is important for brain development and function, and mutations on this gene can alter MeCP2 protein structure or reduce the amount of protein produced.
Previous studies have shown that patients with Rett syndrome may experience mitochondrial dysfunction and its associated manifestations, such as short stature and stunted growth.
Mitochondria are organelles that are the main producers of energy within a cell. These organelles have their own distinct DNA compared with the rest of the cell, and the number of mtDNA copies has been proposed to be a potential biomarker of mitochondrial dysfunction.
Researchers in China investigated the role of mtDNA copy number — the number of mitochondrial DNA copies per cell — in patients with Rett, as well as if it is an indicator of mitochondrial dysfunction and associated with disease severity.
The team analyzed 142 female Rett patients between the ages of 1 and 33 (median age, 3) with various MECP2 mutations. The same number of age- and sex-matched, healthy people were analyzed as the control group. Among the patients, there were 54 MECP2 variants, including 43 disease-causing (pathogenic) variants and 11 variants that were likely pathogenic.
Results showed that patients with Rett syndrome had significantly higher mtDNA copy numbers than their age-matched controls — mean 2.21 versus 2.11, suggesting that “patients had amplification of mtDNA copy number as compared with the control subjects,” the researchers wrote.
No significant correlation was seen between mtDNA copy number and age in this patient cohort.
Patients were then categorized into two groups based on the clinical symptoms of their different MECP2 variants, a low-severity group and a high-severity group. No link was found between mtDNA copy number and clinical severity. There also seemed to be no significant difference between mtDNA copy number and different MCEP2 variants.
Overall, the “data showed that the mtDNA copy number was increased in [Rett] patients as compared with the control subjects, suggesting [Rett] patients might have impairment of energy metabolism.”
The abnormal increase in the mtDNA copy number in these patients may be a compensatory mechanism for a lack of energy, the scientists noted.
Furthermore, “this study supports the hypothesis that high mtDNA copy number may be a common theme in neurodevelopmental diseases,” the researchers wrote, suggesting that “mtDNA copy number can act as a commonly used clinical biomarker to study the mitochondrial functions.”
Further studies, however, are needed to confirm this possibility.