Problems with a key group of enzymes called topoisomerases can have profound effects on the genetic machinery behind brain development and potentially lead to autism spectrum disorder (ASD), according to research. Scientists at the University of North Carolina School of Medicine have described a finding that represents a significant advance in the hunt for environmental factors behind autism and lends new insights into the disorder’s genetic causes.

‘Our study shows the magnitude of what can happen if topoisomerases are impaired,’ said senior study author Mark Zylka, PhD, associate professor in the Neuroscience Center and the Department of Cell Biology and Physiology at UNC. ‘Inhibiting these enzymes has the potential to profoundly affect neurodevelopment — perhaps even more so than having a mutation in any one of the genes that have been linked to autism.’

The study could have important implications for ASD detection and prevention.

‘This could point to an environmental component to autism,’ said Zylka. ‘A temporary exposure to a topoisomerase inhibitor in utero has the potential to have a long-lasting effect on the brain, by affecting critical periods of brain development. ‘

This study could also explain why some people with mutations in topoisomerases develop autism and other neurodevelopmental disorders.

Topiosomerases are enzymes found in all human cells. Their main function is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes.

Most of the known topoisomerase-inhibiting chemicals are used as chemotherapy drugs. Zylka said his team is searching for other compounds that have similar effects in nerve cells. ‘If there are additional compounds like this in the environment, then it becomes important to identify them,’ said Zylka. ‘That’s really motivating us to move quickly to identify other drugs or environmental compounds that have similar effects — so that pregnant women can avoid being exposed to these compounds.’

Zylka and his colleagues stumbled upon the discovery quite by accident while studying topotecan, a topoisomerase-inhibiting drug that is used in chemotherapy. Investigating the drug’s effects in mouse and human-derived nerve cells, they noticed that the drug tended to interfere with the proper functioning of genes that were exceptionally long — composed of many DNA base pairs. The group then made the serendipitous connection that many autism-linked genes are extremely long.

‘That’s when we had the ‘Eureka moment,’’ said Zylka. ‘We realised that a lot of the genes that were suppressed were incredibly long autism genes.’

Of the more than 300 genes that are linked to autism, nearly 50 were suppressed by topotecan. Suppressing that many genes across the board — even to a small extent — means a person who is exposed to a topoisomerase inhibitor during brain development could experience neurological effects equivalent to those seen in a person who gets ASD because of a single faulty gene.

The study’s findings could also help lead to a unified theory of how autism-linked genes work. About 20 percent of such genes are connected to synapses — the connections between brain cells. Another 20 percent are related to gene transcription — the process of translating genetic information into biological functions. Zylka said this study bridges those two groups, because it shows that having problems transcribing long synapse genes could impair a person’s ability to construct synapses.

‘Our discovery has the potential to unite these two classes of genes — synaptic genes and transcriptional regulators,’ said Zylka. ‘It could ultimately explain the biological mechanisms behind a large number of autism cases.’ University of North Carolina School of Medicine

Cancer Research UK scientists have found a gene in mice that could protect against ovarian cancer and, if faulty, may increase the chance of developing the disease, according to research.
This gene, known as Helq, helps repair any damage to DNA that happens when it is copied as cells multiply. So if the gene is missing or faulty, DNA errors could mount up, increasing the chance of cancer developing.
The team, from Cancer Research UK’s London Research Institute, found that mice without either of the two copies of the Helq gene were twice as likely to develop ovarian tumours, as well as becoming less fertile. And even losing just a single copy of the Helq gene was enough to cause a mouse to develop more tumours.
Dr Simon Boulton, senior author from Cancer Research UK’s London Research Institute, said: ‘Our findings show that if there are problems with the Helq gene in mice it increases the chance of them developing ovarian and other tumours. This is an exciting finding because this might also be true for women with errors in Helq, and the next step will be to see if this is the case.
‘If it plays a similar role in humans, this may open up the possibility that, in the future, women could be screened for errors in the Helq gene that might increase their risk of ovarian cancer.’
Dr Julie Sharp, Cancer Research UK’s senior science information manager, said: ‘This study pulls together clues from a series of experiments building a picture of cell faults that could lead to ovarian cancer in women.
‘Ovarian cancer can be hard to diagnose early and treat successfully so the more we know about the causes of the disease, the better equipped we will be to detect and treat it.’ Cancer Research UK

Case Western Reserve researchers have identified a genetic factor that blocks the blood vessel inflammation that can lead to heart attacks, strokes and other potentially life-threatening events.
The breakthrough involving Kruppel-like factor (KLF) 15 is the latest in a string of discoveries from the laboratory of professor of medicine Mukesh K. Jain, MD, FAHA, that involves a remarkable genetic family. Kruppel-like factors appear to play prominent roles in everything from cardiac health and obesity to metabolism and childhood muscular dystrophy.
School of Medicine instructor Yuan Lu, MD, a member of Jain’s team, led the study involving KLF-15 and its role in inflammation. Lu and colleagues observed that KLF-15 blocks the function of a molecule called NF-kB, a dominant factor responsible for triggering inflammation.
This finding reveals a new understanding of the origins of inflammation in vascular diseases, and may eventually lead to new, targeted treatment options.
‘It had been suspected that smooth muscle cells were related to inflammation, but it hadn’t been pinpointed and specifically linked to disease,’ said Jain, Ellery Sedgwick Jr. Chair and director, Case Cardiovascular Research Institute at Case Western Reserve School of Medicine. Jain also is chief research officer for the Harrington Heart & Vascular Institute at University Hospitals Case Medical Center. ‘This work provides cogent evidence that smooth muscle cells can initiate inflammation and thereby promote the development of vascular disease.’
Smooth muscle cells are only one of two major cell types within blood vessels walls. The other cell type, endothelium, has traditionally taken the blame for inflammation, but Jain’s study suggests that both cells are critically important in the development of vascular disease.
The researchers learned that expression of this factor appeared mainly in smooth muscle cells and that levels were markedly reduced in atherosclerotic human blood vessels. To establish causality, the team generated genetically-modified mice where they deleted KLF-15 gene in smooth muscle cells.
‘We expected to see more proliferation of the smooth muscle cells as this is a common response of this cell type in disease,’ Lu said, first author on the paper. ‘Instead, we were surprised to see rampant vascular inflammation and hyper activated NF-kB, the master regulator of inflammation.’
The results offer hope for the development of specific anti-inflammatory therapies for vascular disease. Cholesterol-lowering drugs such as statins have some anti-inflammatory effects, but despite their widespread use, the burden of vascular disease remains high. As statins’ primary role is to lower cholesterol levels, developing additional or more potent anti-inflammatory therapies are needed to compliment statins’ important function.
Jain’s previous research of the KLF family of genetic factors revealed regulator functions in blood vessels. KLF4 was shown to potently inhibit inflammation in the endothelium, the other major cell type in vessels. The current work is first to establish a role for these factors in smooth muscle inflammation. Case Western Reserve University School of Medicine

Obesity gene testing does not put people off weight loss and may help to reduce self-blame, according to a new study by researchers from the Health Behaviour Research Centre at UCL.

Previous studies have shown that genes play a role in a person’s risk of becoming overweight. One gene, called FTO, has been found to have the biggest influence so far.

FTO has two variants, one associated with greater risk of weight gain (A) and one associated with lower risk (T). One in two people carries at least one copy of the A variant. People who inherit two A variants (one from their mother and one from their father) are 70% more likely to become obese than those with two T variants. Even those who inherit one have a higher weight than those with two T variants.

Researchers can now use a gene test for FTO (although this is not yet commercially available). However, it was not known how people would react to finding out the results of the genetic test.
Regardless of gene status or weight, all the volunteers recognised that both genes and behaviour are important for weight control. The results indicate that people are unlikely to believe that genes are destiny and stop engaging with weight control once they know their FTO status.
Some clinicians thought it would help people to become motivated to manage their weight. Others thought that the ‘genes as destiny’ perspective might mean people felt there was nothing they could do about their weight. If people responded fatalistically it could be harmful because diet and exercise are still very important for health and weight control, perhaps even more so if a person is ‘battling against their biology’.

UCL’s Professor Jane Wardle and Susanne Meisel decided to test a small number of volunteers (18) for their FTO status and interview them about their experience. The sample of volunteers included men and women, who spanned the weight range from underweight to obese.

They found that the volunteers were very enthusiastic about receiving their genetic test result. Those who struggled with their weight said that the genetic test result was helpful because it removed some of the emotional stress attached to weight control and relieved some of the stigma and self-blame.

No one reported a negative reaction to the genetic test result, or said it made them feel there was nothing they could do to about their weight.

Susanne Meisel, who led the study said: ‘These results are encouraging. Regardless of gene status or weight, all the volunteers recognised that both genes and behaviour are important for weight control. The results indicate that people are unlikely to believe that genes are destiny and stop engaging with weight control once they know their FTO status. Although they knew that FTO’s effect is only small, they found it motivating and informative. We are now doing a larger study to confirm whether more people react in the same way.’ University of College London

Case Western Reserve University is part of a landmark study that has discovered four novel gene variations which are associated with blood pressure. The 19-site meta-analysis, involving nearly 30,000 African-Americans, also found that the set of genetic mutations are also associated with blood pressure across other populations.
Epidemiology and biostatistics professor Xiaofeng Zhu, PhD, is co-senior author of the paper. The Continental Origins and Genetic Epidemiology Network (COGENT) consortium conducted the research, which is the largest genome-wide association study of blood pressure in individuals of African ancestry. Most gene discovery studies to date have been performed using individuals of European ancestry. Previous genome-wide association studies using samples from individuals of African descent failed to detect any replicable genes associated with blood pressure.
‘In addition to their disproportionate suffering, hypertension occurs earlier in life for African-Americans compared to individuals of other ancestries,’ Zhu explained. ‘Therefore, it is important to study this population to better understand genetic susceptibility to hypertension.’
Zhu and his colleagues also confirmed that previous findings regarding other genes whose presence correlates with increased hypertension risk.
‘Although it is unknown how the genes regulate blood pressure,’ Zhu added, ‘our findings contribute to better understanding of blood pressure pathways that can lead to future development of drug target for hypertension and may guide therapy for clinical care.’
Experts estimate genetic make-up accounts for roughly 40-50 percent of individuals’ susceptibility to hypertension. Other factors associated with the disease include lifestyle, diet, and obesity. Compared to Americans of European-ancestry, African-Americans’ increased hypertension prevalence contributes to a greater risk of stroke, coronary heart disease, and end-stage renal disease.
‘We anticipated that individuals of African ancestry share similar biology to other populations. However, differences in genomic make-up between African ancestry and other populations have uncovered additional genes affecting blood pressure, in addition to genetic variants that are specific to individuals of African ancestry,’ said Nora Franceschini, MD, MPH, nephrologist and research assistant professor of epidemiology at the University of North Carolina at Chapel Hill and first author on the paper.
The next phase of study involving the newly discovered gene mutations will investigate their function using human blood samples at the molecular level. Zhu and his colleagues have begun conducting additional research to determine whether the newly identified genes respond to existing hypertension medications. Individuals typically respond differently to a given medication depending on which gene mutation they carry. The more information researchers gather, the greater opportunity clinicians will have prescribed the drug that is most efficacious based on the patient’s specific mutation.
‘The research findings do not have immediate implications for treatment, but the hope is that discovering genes associated with disease risks will bring scientists closer to biological pathways and may suggest useful targets for new treatments,’ said geneticist Brendan J. Keating, DPhil, one of co-senior authors of the paper, of The Center for Applied Genomics at The Children’s Hospital of Philadelphia and faculty at the Department of Pediatrics at the University of Pennsylvania. Case Western Reserve University School of Medicine