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Studies Point to Topoisomerase Gene Role in Neurodevelopmental Disorders

NEW YORK (GenomeWeb News) – Studies by two independent research teams published online yesterday in Nature Neuroscience suggest a single gene — the enzyme-coding gene called TOP3B — contributes to processes related to schizophrenia and to a syndrome associated with autism spectrum disorder and intellectual disability.

Researchers from Germany, the UK, Finland, the US, and Iceland relied on a combination of genetic and biochemical experiments to dig up and begin delving into the functional consequences of a chromosome 22 deletion affecting TOP3B. Though rare in the general population, the deletion turns up far more frequently than usual in a population in Finland's northeast, where it appears to contribute to the risk of symptoms associated with schizophrenia and the neurodevelopmental condition Fragile X syndrome.

"[N]ot only have we uncovered vital information about the biology behind schizophrenia, but we have also linked this same biological process to a disorder associated with learning difficulties," co-senior author Aarno Palotie, a researcher affiliated with the Wellcome Trust Sanger Institute, the Broad Institute, and Finland's Institute for Molecular Medicine, said in a statement.

"Our findings offer great hope for future studies into the genetic basis of schizophrenia and other brain disorders," he added, "potentially finding new drug targets against them."

The study stemmed from the realization that neurodevelopmental disease rates vary noticeably within Finland in ways that appear to coincide with the country's migration history.

With this in mind, researchers focused in on a founder population in northeast Finland where schizophrenia rates are known to be roughly three times higher than those documented in other parts of the country.

Through an array-based SNP analysis of samples from 173 individuals in that population and nearly 1,600 individuals from across Finland, researchers searched for medium-sized deletions that might help explain some of the risk stratification.

The search led to two deletions that appear more frequently in the northern population. The first, a chromosome 4 deletion, didn't affect any known coding genes. The other turned up in a portion of chromosome 22 previously implicated in schizophrenia and developmental delay.

In the northern Finnish population tested, the latter deletion appeared to be part of a shared haplotype involving around 289,000 bases of chromosome 22 sequence.

When they folded in existing genotype data for 185 Finnish individuals with schizophrenia and almost 750 without, the researchers saw that the chromosome 22 deletion was especially common in the schizophrenia group.

The chromosome 4 deletion, on the other hand, was found about as often in controls as in schizophrenia cases — a pattern they subsequently confirmed using case and control data for thousands more individuals from Finland and beyond.

The chromosome 22, but not the chromosome 4, deletion showed ties to cognitive conditions, too. Genotyping profiles available for almost 4,900 individuals of a Finnish birth cohort indicated that the deletion was enriched in individuals with learning problems or more severe forms of intellectual delay.

Likewise, when the team looked specifically at data for several hundred individuals with schizophrenia, it saw that those who carried the deletion appeared more prone to learning problems.

The stretch of affected chromosome 22 sequence included TOP3B, a gene coding for the type of topoisomerase enzyme that's typically associated with unwinding of the DNA double helix.

Through a series of follow-up experiments on the TOP3-beta protein encoded by the gene, researchers found clues that TOP3B may contribute to brain development or function via a pathway related to messenger RNA metabolism and translation.

In particular, their biochemical experiments indicated that the topoisomerase interacts with RNA rather than DNA as previously believed. The absence of this enzyme may partially disrupt normal interactions by the Fragile X syndrome protein FMRP, too, they found, perhaps explaining some of the neurodevelopmental symptoms and disease risks observed in individuals carrying the newly detected deletion.

"These two disorders, schizophrenia and Fragile X syndrome, although they may seem drastically different, share key features, particularly the cognitive impairment that is frequently associated with both conditions," co-corresponding author Nelson Freimer, a neurobehavioral genetics researcher at the University of California at Los Angeles, said in a statement. "So, it is not unexpected that they could share some of the same biological processes."

In an accompanying Nature Neuroscience study, investigators based at the National Institute on Aging and other centers in the US, China, and Canada present further evidence for interactions between the Top3-beta protein, the Fragile X syndrome player FMRP, and other proteins in the same mRNA-interacting complex.

Based on their cell lines experiments, for instance, members of that team found that mutations in the FMRP gene FMR1 seem to muddle Top3-beta's ability to adeptly bind the mRNA interacting complex, where it normally interacts with a number of mRNAs implicated in neuronal function and conditions such as schizophrenia and autism.

"Our findings suggest that Top3-beta acts as an RNA topoisomerase and works with FMRP to promote the expression of mRNAs that are crucial for neurodevelopment and mental health," NIA researchers Sige Zou and Weidong Wang, the study's co-corresponding authors, and their colleagues wrote.

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