A gene linked to autism spectrum disorders that was manipulated in two lines of transgenic mice produced mature adults with irreversible deficits affecting either learning or social interaction.
The findings have implications for potential gene therapies but they also suggest that there may be narrow windows of opportunity to be effective, says principal investigator Philip Washbourne, a professor of biology and member of the University of Oregon’s Institute of Neuroscience.
The research, reported by an 11-member team from three universities, targeted the impacts of alterations in the gene neuroligin 1 — one of many genes implicated in human autism spectrum disorders — to neuronal synapses in the altered mice during postnatal development and as they entered adulthood. One group over-expressed the normal gene, the other a mutated version.
Mice with higher-than-normal levels of the normal gene after a month had skewed synapses at maturity. Many were larger, appearing more mature, than normal. In these mice, Washbourne said, there were clear cognitive problems. ‘Behaviour was just not normal. They didn’t learn very well, and they were slower to learn, but their social behaviour was not impacted.’
Mice over-producing a mutated version of the gene reached adulthood with structurally immature synapses. ‘They were held back in development and behaviour — the way they behave in terms of learning and memory, in terms of social interaction,’ he said. ‘These were adult mice, three months old, but they behaved like normal mice at four weeks old. We saw arrested development. Learning is a little bit better, they are more flexible just like young mice, they learn faster, but their social interaction is off. To us, this looked more like Asperger’s syndrome.
‘So with the same gene, doing two different manipulations — over-expressing the normal form or over-expressing a mutated form — we’ve gone to two different ends of the autism spectrum,’ said Washbourne, whose lab focuses on basic synapse formation and what goes wrong in relationship to autism. Work has been done in both mice and zebra fish.
‘We made these mice so that we can turn the genes on and off as we want,’ Washbourne said. ‘Using an antibiotic, doxycycline, it turns off these altered genes that we inserted into their chromosomes. While on doxycycline, the mice are absolutely normal.’
However, if the inserted gene was turned off after the completion of development, mice still showed altered synapses and behaviour. This result suggests that any kind of gene therapy may have to be applied to individuals with autism early on.
Effects seen in the social behaviour of mice with the mutated gene, he said, are not unlike observations reported by parents of many autistic children. While normal mice prefer to engage with new mice entering their world rather than familiar others, or even a new inanimate object, these mice split their time equally. ‘It’s not a deficit in memory regarding which mouse is which, it’s more a weighting of their interaction. Does that mean they are autistic? I don’t know, but if you talk to parents of autistic children, one of the frustrating things they report is that their children treat complete strangers in exactly the same way that they treat them.’
While the findings provide new insights, Washbourne said, any translation into treatment could be decades away. ‘A problem with autism is there are many different genes potentially involved. It could be that some day, if you are diagnosed with autism, a mouth swab might allow for the identification of the exact gene that is mutated and allow for targeted therapy,’ he said. ‘Genome sequencing already has turned up subtle mutations in lots of genes. Autism might be like cancer, with hundreds of potential combinations of faulty genes.’ University of Oregon

Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.
The results suggest a monthly window of opportunity that could potentially be targeted in efforts to prevent common mental health problems developing in women. The research is the first to show a potential link between psychological vulnerability and the timing of a biological cycle, in this case ovulation.

A common symptom of mood and anxiety problems is the tendency to experience repetitive and unwanted thoughts. These ‘intrusive thoughts’ often occur in the days and weeks after a stressful experience.
In this study, the researchers examined whether the effects of a stressful event are linked to different stages of the menstrual cycle. The participants were 41 women aged between 18 and 35 who had regular menstrual cycles and were not using the pill as a form of contraception. Each woman watched a 14-minute stressful film containing death or injury and provided a saliva sample so that hormone levels could be assessed. They were then asked to record instances of unwanted thoughts about the video over the following days.
There is actually a fairly narrow window within the menstrual cycle when women may be particularly vulnerable to experiencing distressing symptoms after a stressful event.
‘We found that women in the ‘early luteal’ phase, which falls roughly 16 to 20 days after the start of their period, had more than three times as many intrusive thoughts as those who watched the video in other phases of their menstrual cycle,’ explains author Dr Sunjeev Kamboj, Lecturer in UCL’s Department of Clinical, Educational and Health Psychology.
‘This indicates that there is actually a fairly narrow window within the menstrual cycle when women may be particularly vulnerable to experiencing distressing symptoms after a stressful event.’
The findings could have important implications for mental health problems and their treatment in women who have suffered trauma.
‘Asking women who have experienced a traumatic event about the time since their last period might help identify those at greatest risk of developing recurring symptoms similar to those seen in psychological disorders such as depression and post-traumatic stress disorder (PTSD),’ said Dr Kamboj.

‘This work might have identified a useful line of enquiry for doctors, helping them to identify potentially vulnerable women who could be offered preventative therapies,’ continued Dr Kamboj. University College London

Researchers have identified a set of genes that allow melanoma cells, a type of cancer cell, to change rapidly between two shapes to escape from the skin and spread around the body. This new research – funded by the Wellcome Trust, Cancer Research UK and the US National Institutes of Health – could pave the way for scientists to develop desperately needed drugs for malignant melanoma, the deadliest form of skin cancer, which kills more than 2200 people every year.
The most dangerous aspect of melanoma is its ability to spread, or become malignant, to other parts of the body in the later stages of disease. This most often includes the liver, lungs and brain.
Dr Chris Bakal, a Wellcome Trust research fellow at the Institute of Cancer Research, London, explains: ‘We already knew that metastatic melanoma cells, or cells that are able to spread through the body, have to be able to adopt different shapes so that they can squeeze their way between healthy cells and move around the body.
‘The cells have to become rounded to travel through the bloodstream or invade soft tissues such as the brain, but they take on an elongated shape to travel through harder tissues like bone. But until now, we knew hardly anything about how the cells assume either of these shapes and how they switch between the two.’
To investigate this, researchers at the Institute of Cancer Research, London, and Weill Cornell Medical College in Houston started out by looking at fruit fly cells. They found that under normal conditions, the fruit fly cells grew in five different shapes. By switching off specific genes, they were able to change the mix of shapes among the fruit fly cells and identify several different genes that control a cell’s shape-shifting ability.
When they looked in human melanoma cells, they found that the human versions of these genes had a similar effect. In particular, they noted that switching off a gene called PTEN increased the proportion of cells that were elongated rather than rounded.
PTEN is a gene that is also involved in stopping healthy cells from becoming cancer cells, a so-called ‘tumour suppressor’ gene. This particular gene is switched off in around 1 in 8 melanoma patients and in almost half of melanoma patients who carry a mutation in another cancer gene called BRAF.
‘We think that metastatic melanoma cells lose their PTEN function so that they can increase their shape-shifting ability, which in turn enables them to move to many different tissues within the body. It’s early days, but taken together our findings offer new opportunities to develop drugs to try and stop the spread of melanoma,’ Dr Bakal added.
Dr Julie Sharp, Senior Science Communications Manager at Cancer Research UK, said: ‘This is still early research, but it gives us a better grasp of the way cancer cells behave in the body. By mimicking these conditions, our researchers are learning more about melanoma and bringing us closer to beating it. Wellcome Trust

French scientists have discovered that supposedly rare mutations in the mitochondria, the ‘power plants’ of human cells responsible for creating energy, account for more than 7% of patients with a mitochondrial disease manifesting itself as a respiratory deficiency. Their data emphasise the need for comprehensive analysis of all the mitochondrial DNA (mtDNA) in patients suspected as having a mitochondrial disease, and this should include children, a researcher will tell the annual conference of the European Society of Human Genetics.
Dr. Sylvie Bannwarth and Professor Véronique Paquis, from the Hôpital Archet 2, Nice, France, together with colleagues from the ten diagnostic centres that make up the French Mitochondrial Disease Network, investigated 743 patients who were suspected of having a respiratory chain disorder caused by defective mitochondria, but who did not carry a common mtDNA mutation. Mitochondrial diseases, which can be very severe, are estimated to affect one child in every 5000, and are usually untreatable. However, prompt diagnosis can help clinicians to prescribe treatment to alleviate secondary symptoms.

‘We examined the relationship between clinical presentation of disease, age at onset, and the localisations of mutations. Our results showed that, in the French population, clinical presentations that are not associated with common mtDA mutations begin mainly before adulthood, and that neuromuscular problems are the most common manifestation of such mutations’, says Dr. Bannwarth.

‘We found that early onset disease was significantly associated with mutations in genes that code for proteins, while late onset disorder were associated with mutations in tRNA genes, and that two genes represent ‘hotspots’ for disease-causing mutations. Knowing the prevalence of these rare mutations is essential if we are to be able to improve the diagnosis of these diseases.’

There are very many mitochondrial diseases, and they manifest themselves in a large number of different ways. They can involve muscle weakness, neurological disease, respiratory, gastrointestinal and cardiac problems, and strokes. Many are degenerative, while some are relatively static.

One of the two techniques used for screening the entirety of an individual’s mtDNA was developed by Dr. Bannwarth. The use of such techniques can aid not just in diagnosis, but also in genetic counselling and prenatal diagnosis for mitochondrial disease. Up to now the study of mtDNA mutations has usually been restricted to the detection of deletions and a few common mutations, but without any data about the prevalence of rare mutations and their associated phenotypes (characteristics or traits).

‘With the advent of Next Generation Sequencing techniques, screening all mtDNA is now feasible, and this means that we can detect both common and rare mutations as well as deletions. For example, in the patients we studied we found that Leigh syndrome – a rare disorder that affects the central nervous system – was found in 41% of patients with rare mtDNA mutations. Had we not screened all of the mtDNA, including the rare mutations, we would not have known this’, says Dr. Bannwarth. ‘This is clearly a big aid to accurate diagnosis and we hope that our results will underline the importance of comprehensive mtDNA screening.’ EurekAlert

Although a family history of Alzheimer’s disease is a primary risk factor for the devastating neurological disorder, mutations in only three genes – the amyloid precursor protein and presenilins 1 and 2 – have been established as causative for inherited, early-onset Alzheimer’s, accounting for about half of such cases. Now Massachusetts General Hospital (MGH) researchers have discovered a type of mutation known as copy-number variants (CNVs) – deletions, duplications, or rearrangements of human genomic DNA – in affected members of 10 families with early-onset Alzheimer’s. Notably, different genomic changes were identified in the Alzheimer’s patients in each family.
The study was conducted as part of the Alzheimer’s Genome Project – directed by Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) and a co-discoverer of the first three early-onset genes – and was supported by the Cure Alzheimer’s Fund and the National Institute of Mental Health (NIMH).
‘We found that the Alzheimer’s-afflicted members of these families had duplications or deletions in genes with important roles in brain function, while their unaffected siblings had unaltered copies of those genes,’ says Basavaraj Hooli, PhD, of the Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, lead author of a report that has been published online in Molecular Psychiatry. ‘Since our preliminary review of the affected genes has provided strong clues to a range of pathways associated with Alzheimer’s disease and other forms of dementia, we believe that further research into the functional effects of these CNVs will provide new insights into Alzheimer’s pathogenesis.’ Hooli is a research fellow in Neurology at Harvard Medical School.
Most studies searching for genes contributing to Alzheimer’s risk have looked for variants in a single nucleotide, and while thousands of such changes have been identified, each appears to have a very small impact on disease risk. Recently research has found that CNVs – in which DNA segments of varying lengths are deleted or duplicated – have a greater impact on genomic diversity than do single-nucleotide changes. This led Tanzi and his team to search for large CNVs in affected members of families with inherited Alzheimer’s disease. ‘These are the first new early-onset familial Alzheimer’s disease gene mutations to be reported since 1995, when we co-discovered the presenilins. As with those original genes, we hope to use the information gained from studies of the new Alzheimer’s mutations to guide the development of novel therapies aimed at preventing and treating this devastating disease.’ Tanzi explains.
The investigators reviewed genomic data from two sources – the NIMH Alzheimer’s Disease Genetics Initiative and the National Cell Repository for Alzheimer’s Disease – and focused on 261 families with at least one member who developed Alzheimer’s before the age of 65. Using a novel algorithm they had developed for analyzing CNVs, the researchers identified deletions or duplications that appeared only in affected members of these families. Two of these families had CNVs that included the well-established amyloid precursor protein gene, but 10 others were found to have novel Alzheimer’s-associated CNVs, with different gene segments being affected in each family.
While none of the novel variants have previously been associated with Alzheimer’s disease, most of them affect genes believed to be essential to normal neuronal function, and several have been previously associated with other forms of dementia. For example, one of the identified CNVs involves deletion of a gene called CHMP2B, mutations of which can cause ALS. In another family, affected members had three copies of the gene MAPT, which encodes the tau protein found in the neurofibrillary tangles characteristic of Alzheimer’s. Mutations in MAPT also cause frontotemporal dementia.
Hooli explains, ‘Potential clinical application of the findings of this study are not yet clear and require two additional pieces of information: similar studies in larger groups of families with inherited Alzheimer’s to establish the prevalence of these CNVs and whether the presence of one ensures development of the disease, and a better understanding of how these variants affect neuronal pathways leading to the early-onset form of Alzheimer’s disease.’ Massachusetts General Hospital