A group of people with fatal H1N1 flu died after their viral infections triggered a deadly hyperinflammatory disorder in susceptible individuals with gene mutations linked to the overactive immune response, according to a study.

Researchers at Cincinnati Children’s Hospital Medical Center, the University of Alabama Birmingham and Children’s of Alabama led the study. They suggest people with other types of infections and identical gene mutations also may be prone to the disorder, known as reactive HLH (rHLH), or haemophagocytic lymphohistiocytosis.

HLH causes the immune system to essentially overwhelm the body with inflammation that attacks vital organs, often leading to death. Study authors raise the possibility of screening children for HLH genes to identify those who may be at risk during a viral infection.

“Viruses that cause robust immune responses may be more likely to trigger rHLH in genetically susceptible people,” said Randy Cron, M.D., Ph.D., a senior investigator on the study and physician in paediatric rheumatology at UAB and Children’s of Alabama. “Prenatal screening for mutations in common HLH-associated genes may find as much as 10 percent of the general population who are at risk for HLH when an inflammation threshold is reached from H1N1 or other infection triggers.”

This study is the first to identify mutations of HLH-associated genes in H1N1 cases where patients had clinical symptoms of rHLH and a related condition called macrophage activation syndrome, or MAS. An outbreak of H1N1 in 2009 turned into a global pandemic. H1N1 has since become part of the viral mix for the annual flu season and preventive vaccine, the authors note. University of Alabama Birmingham

ETH researchers have discovered a molecule in liver cells that controls the release of fat into the bloodstream. This “lock keeper” is present in large quantities in overweight people and leads indirectly to vascular narrowing.

Anyone attending Munich’s famous Oktoberfest will know it can leave physical traces; fatty foods and plenty of alcohol cause the liver to work overtime. This organ stores a portion of any fat consumed (and also converts alcohol to fat), but releases it again once the revelry is over.

However, should the excesses continue – and if they are not offset by exercise and sport – the person becomes overweight and diabetic, leading to a condition known as fatty liver. If corrective action is taken in time, the liver can usually recover completely from its fatty degeneration. In severe cases the organ becomes inflamed – a condition that is almost impossible to treat.

Fatty liver is also associated with elevated blood fat values. When the liver becomes fatty it seeks relief by releasing fat into the bloodstream, including “good” fat in the form of high density lipoprotein (HDL), but also “bad” fat, such as low density lipoprotein (LDL), and its precursor, very low density lipoprotein (VLDL).
If the concentration of LDL and VLDL in the blood is too high, vascular constriction forms through atherosclerotic plaques. Should a plaque detach itself, there is a real risk of a vascular blockage, which results in a heart attack or stroke.

Markus Stoffel, Professor of Molecular Health Sciences at ETH Zurich, has been working with his team in collaboration with other scientists in Switzerland, Germany and the US to gain a closer understanding of the connection between excess weight, fatty liver and vascular constriction. And this has led to a surprising discovery: the scientists succeeded to identify a protein in liver cells known as vigilin, which acts as a kind of “lock keeper”. It regulates the release of fats, including VLDL, from the liver into the bloodstream.

The researchers found vigilin in large quantities in the liver cells of overweight mice – and humans. “The level of vigilin in the liver cells of people with fatty livers bears a strong correlation with the percentage of fat in the liver,” explains Stoffel. “In other words, the more fat liver cells contain, the higher the quantity of vigilin.”

In a study the ETH professor and his co-workers demonstrate that the primary function of vigilin is to regulate proteins that transport fat out of the liver. However, the molecule does not bind directly to these transport proteins, but rather to certain points of the associated messenger RNA.
The messenger RNA is the transcription of a gene. It represents the construction plan for the associated protein and is transported from the cell nucleus to the ribosomes. These molecular machines use the messenger RNA to build the protein.

The assumption is that vigilin supplies the ribosomes with the messenger RNA to which it is bound. But it is not just a transport vehicle, it also accelerates production of the associated protein.

One of these proteins “promoted” by vigilin is apolipoprotein B (ApoB), which is responsible for exporting triglycerides from the liver. Triglycerides also promote vascular calcification when present in concentrated form in overweight people.

In order to establish the causal relationship between vigilin and vascular calcification, the researchers stemmed formation of this protein in the livers of mice using a new process of RNA interference. As a consequence of this intervention, these animals suffered far less from atherosclerosis than animals who processed vigilin normally. By contrast, increased vigilin formation led to substantial deposits in the vessels.

“Vigilin intervenes at the level of gene regulation, which has barely been investigated to date,” says Stoffel. Our knowledge of how genes are regulated at the level of DNA is improving all the time. And the regulatory processes by which DNA templates are transcribed into messenger RNA are increasingly understood. But regulation of the step from messenger RNA to protein is something we know much less about. This makes the knowledge that vigilin has a regulatory function at this level all the more valuable. And researchers are particularly excited by the fact that vigilin is the first RNA-binding protein found in the context of fatty livers and diabetes.

ETH Zurich www.ethz.ch/en/news-and-events/eth-news/news/2016/09/vigilin-the-lock-keeper.html

The babies of obese women who develop gestational diabetes are five times as likely to be excessively large by six months of pregnancy, according to new research led by the University of Cambridge. The study, which shows that excessive foetal growth begins weeks before at-risk women are screened for gestational diabetes, suggests that current screening programmes may take place too late during pregnancy to prevent lasting health impacts on the offspring.

Gestational diabetes is a condition that can affect women during pregnancy, with those who are obese at greater risk. As well as affecting the mother’s health, the condition also causes the unborn child to grow larger, putting the mother at risk during childbirth and increasing the likelihood that her offspring will develop obesity and diabetes during later life. The condition can usually be controlled through a combination of diet and exercise, and medication if these measures fail.

Women are screened for the condition through a blood glucose test at around 8-12 weeks into pregnancy. Current guidelines in the UK and the USA recommend that mothers found to be at greatest risk should then be offered a full test at between 24 and 28 weeks into pregnancy; however, in practice the majority of women are screened at the 28 week mark.

Researchers at the Department of Obstetrics & Gynaecology at the University of Cambridge analysed data from the Pregnancy Outcome Prediction study, which followed more than 4,000 first time mothers using ultrasound scans to assess the growth of their babies in the womb. They measured the abdominal and head circumference of the foetuses and compared the growth in women who developed gestational diabetes with those who did not.

Of the 4,069 women studied, 171 (4.2%) were diagnosed with gestational diabetes at or beyond 28 weeks. The researchers found no association between the size of the child at 20 weeks and the mother subsequently developing gestational diabetes. However, they found that the foetuses of women subsequently diagnosed with gestational diabetes grew excessively prior to diagnosis, between 20 and 28 weeks. Hence, the babies were already large at the time of diagnosis, and their findings suggest that the onset of foetal growth disorder in gestational diabetes predates the usual time of screening.

The researchers also studied women who were obese, as it is well recognised that maternal obesity is a risk factor for childhood obesity. Even in the absence of diabetes, the babies of obese women were also twice as likely to be big at 28 weeks. The combination of obesity and gestational diabetes was associated with an almost 5-fold risk of excessive foetal growth by the 28 week scan.

“Our study suggests that the babies of women subsequently diagnosed with gestational diabetes are already abnormally large by the time their mothers are tested for the disease,” says Dr Ulla Sovio from the Department of Obstetrics and Gynaecology at the University of Cambridge, the study’s first author. “Given the risk of complications for both mother and child from gestational diabetes, our findings suggest that screening women earlier on in pregnancy may help improve the short and long term outcomes for these women.

“Early screening may be particularly beneficial for obese women, as fetal growth is already abnormal by 20 weeks among these women. Any intervention aimed at reducing the risk of abnormal birthweight in the infants of obese women may need to be implemented even earlier.”

Senior author Professor Gordon Smith, also from the University of Cambridge, adds: “We know that the offspring of women with gestational diabetes are at increased risk of childhood obesity, but so far no clinical trials have successfully demonstrated that screening and intervention in pregnancy reduces this risk. Our study suggests a possible explanation: screening and intervention is taking place when the effects of gestational diabetes are already manifested in the foetus. Cambridge University

Microcephaly is a rare disorder that stunts brain development in utero, resulting in an abnormally small head. The Zika virus is one environmental cause of this devastating condition, but genetic defects can cause microcephaly, too. A new Duke University study examining three genetic causes of microcephaly in mice suggests one common mechanism through which the disorder could arise.

The study offers a new window into early, critical stages of brain development, and may improve understanding of the diverse causes of microcephaly and other neurodevelopmental disorders, including autism.

“We’re excited about this study because, by stepping back and looking at the basic mechanistic routes to microcephaly, we hope to understand how Zika infection causes microcephaly,” said the study’s senior investigator Debra Silver, an assistant professor of molecular genetics and microbiology at the Duke University School of Medicine.

In the new study, Hanqian Mao, a graduate student in Silver’s lab, created three mouse models of microcephaly by cutting the levels of each of three genes — Magoh, Rbm8a and Eif4a3 — by half during a critical time in brain development. All three types of mice developed a smaller cerebral cortex, the part of the brain responsible for memory and thought.

Then, Mao screened for any changes in mRNA and protein levels that could also contribute to the underdeveloped brains. One change that stood out involved a protein called p53, which accumulated in each of the mutant brains. The group hypothesized that too much p53 could cause developing cells to die.

To test the involvement of p53 in microcephaly, Duke postdoctoral fellow John McMahon suppressed it in each of the three types of mice. By blocking p53 at a crucial point in development, the team was able to trigger the brains to partially or fully recover to normal size, suggesting that p53 or its signalling partners might be considered as new therapeutic targets for microcephaly.

“What we don’t know yet is exactly how our microcephaly-causing genes are regulating p53 and other changes in the brain, and that’s going to be the next big question,” Silver said.

The genes Magoh, Rbm8a and Eif4a3 are related to one another in that they bind together on specific spots on RNA and affect its processing to become protein. Although the triad is expressed in every cell of the body, it is more abundant in brain tissue.

“Our results suggest that the molecular complex is a master regulator of cortical development, because it’s regulating critical genes in stem cells, which must divide and then start making neurons,” said Silver, who is also a member of the Duke Institute for Brain Sciences.

“If you have problems at this early stage, you don’t get enough stem cells. And then the stem cells themselves can’t go on to make neurons. That’s where you get microcephaly,” Silver added.

Importantly, disruptions in the genes Rbm8a and Eif43 have already been linked to human cases of intellectual disability, and Rbm8a has been associated with microcephaly and autism in people.

“That’s another reason that identifying the downstream molecules of these genes is really important,” Silver said, adding that her team has some of the only mouse models in which it is possible explore those questions.

Duke University today.duke.edu/2016/09/genetic-causes-small-head-size-share-common-mechanism

Two gene mutations that trigger a retinal disease that causes blindness in one in 5,000 males have been mapped, leading to the potential for new therapeutic treatments.

Researchers from The University of Manchester undertook a structural analysis of X-linked Retinoschisis (XLRS), a genetic disease leading to a type of macular degeneration in which the inner layers of the retina split causing severe loss of vision and gradual blindness. Currently, there is no effective treatment for XLRS, with research focused on understanding how the disease occurs in the retina.

XLRS is caused by mutations in the retinal protein retinoschisin. The protein plays a crucial role in the cellular organisation of the retina, assembling itself to form paired octameric (consisting of eight retinoschisin) rings. The rings each resemble an 8-bladed propeller. This new structural insight yielded important clues into how retinoschisin performs its crucial role in the retina and spurred efforts to investigate what happens to this structure when it is mutated in XLRS.

Using a cryo-electron microscope, the team examined the paired rings as well as the effects on the rings of two XLRS-causing mutations. The effects of these mutations, despite being reported to cause the disease, were unknown and may offer explanations on how the normal protein functions in the retina.

Clair Baldock, Professor of Biochemistry at The University of Manchester and lead author of the research team’s resulting paper, said the cryo-electron microscopy allowed them to identify the location of the mutations on the rings.

“We found that one disease-causing mutation sits in the interface between the octamer rings, causing retinoschisin to be less stable. The other mutation is on the propeller tip which we think is a novel interaction site for other binding proteins in the retina.”

As well as identifying the mutations and precisely mapping their locations, the research team held out the possibility that future work could lead to genetic interventions and treatments, which could limit or prevent the damage caused by XLRS.

“XLRS is a promising candidate for gene therapy, so our findings on these two different classes of mutations will be informative for future therapeutic strategies,” concluded Professor Baldock.

University of Manchesterwww.manchester.ac.uk/discover/news/genetic-mutations-that-lead-to-macular-degeneration-blindness-mapped-by-new-research/