New research from the lab of Adrian Bird, a molecular geneticist at the University of Edinburgh, Scotland, reveals that abnormally high levels of Uqcrc1 may be causative in Rett Syndrome.
“This is the first time a mitochondrial gene has been linked to Rett Syndrome,” says Dr. Bird. This research, which was funded in part by the Rett Syndrome Research Foundation, appears in the July issue of the journal Molecular and Cellular Biology.
Rett Syndrome (RTT), a devastating neurological disorder, strikes 1 in 10,000 young children, almost all of them girls. In fact, RTT is the leading genetic cause of severe impairment in girls. Symptoms include neuromuscular problems, autonomic dysregulation, seizures and seizure-like episodes, stereotypical hand movements and the inability to speak. Many children are wheelchair-bound, scoliosis is common, and though the majority live to adulthood, they require total care for every aspect of life.
RTT, which is an autism-spectrum disorder, is caused by mutations in a gene called MECP2. Previous research has shown that the protein made by MECP2 is a methylation-sensitive transcriptional repressor, and scientists have been searching for downstream repressed genes. Several have been identified, the best known being brain-derived neurotrophic factor, or BDNF, which normally promotes neuronal growth. To find other genes that MECP2 controls, Bird and other colleagues turned to male mice in which MECP2 has been knocked out. These animals are born healthy but begin to walk and breathe abnormally around 6 weeks of age, and start dying off at about 10 weeks (the average lifespan of a mouse is 2 years). The team compared the mutant transcriptome to normal transcriptome in search of differential expression as a function MECP2 loss.
First, Co-author Skirmantas Kriaucionis, now at Rockefeller University in New York City, purified the mRNA (representative of around 10,000 genes) from the brains of mutant mice that were almost 10 weeks old. Compared to normal animals of the same age, the team found more RNA produced by seven genes and less RNA made by three. Then Kriaucionis examined the meRNA produced by those 10 genes in the brains of mice that had only just started coming down with symptoms, at about 7 to 8 weeks of age. Three of the genes were overexpressed.
The team reasoned that these three genes played greater roles in the disorder because they went awry earliest. They decided to focus on Uqcrc1 because much was already known about it, including its role in the mitochondrial energy cycle.
Mitochondria make energy in four steps. Uqcrc1 protein works at the third step in the chain, called complex III. If the researchers supplied precursors that are used by mitochondria before the third step, the mitochondria from the mutant animals made significantly more ATP than the normal mitochondria. If they supplied precursors that are used after complex III, the mutant mitochondria made the same amount as normal organelles.
This suggested that overabundance of Uqcrc1 in complex III resulted in mitochondria cranking out more ATP than the mutant animals needed. "More sounds better but it isn't necessarily that way," says Bird. "Mitochondria are exquisitely regulated machines, so any deviation from normality is likely to be bad."
To find out if Uqcrc1 was to blame for the mitochondrial defects, the team overexpressed the protein in cultured neuronal cells. They isolated mitochondria and repeated the production tests. The mitochondria from the cultured cells behaved like the mutant brain mitochondria. "What we wanted to know is if the overexpression of this gene was solely responsible for the overactive mitochondria. And the data said it's likely to be," says Bird. He adds that additional experiments are needed to link the mitochondrial abnormalities to the symptoms found in the mutant mice. The researchers also caution that similar defects need to be looked for in humans.
"Our findings provide a mechanism for how a mutation in MECP2 could result in abnormal mitochondrial function," says Kriaucionis.
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