Researchers from Sainte-Justine University Hospital Center and University of Montreal have identified several novel genes that make some children more efficient than others in the way their immune system responds to malaria infection. This world-first in integrative efforts to track down genes predisposing to specific immune responses to malaria and ultimately to identify the most suitable targets for vaccines or treatments was published by lead author Dr. Youssef Idaghdour and senior author Pr. Philip Awadalla, whose laboratory has been performing world-wide malaria research for the past 13 years.
‘Malaria is a major health problem world-wide, with over 3 billion individuals at risk and hundreds of thousands of deaths annually, a majority of which are African children under the age of 5. Why are some children prone to infection, while others are resistant and efficiently fight the disease? These are the questions we sought to answer with our study’, Idaghdour says.
However, to succeed where many other studies have failed, the team used an approach different from the classic in vitro one, where the genome is analysed using cells grown in a laboratory. Instead, they used an in vivo approach, analysing blood samples of children from the Republic of Benin, West Africa, collected with the help of collaborators in the city of Cotonou and the nearby village of Zinvié. ‘This approach allowed us to identify how the ‘environment’ engages in an arms race to define the clinical course of the disease, in this case the environment being the number of parasites detected in the child’s blood running against the genetic make-up of the infected child’, Idaghdour explains.
‘We used an innovative combination of technologies that assessed both genetic variation among children and the conditions in which their genes are ‘expressed’. By doing so, we increased the power of our analysis by permitting us not only to detect the mutations, but also to capture their effect depending on how they affect genes being turned ‘on’ or ‘off’ in presence of the parasite’, Awadalla explains. ‘Our approach made us successful, where million-dollar studies have failed in the past. There has never been this many genes associated with malaria discovered in one study.’
This major milestone in understanding how the genetic profile affects the ability of children to cope with infection could pave the way to the development of low-cost genetic profiling tests in a not so far future. ‘Accurate diagnosis of the infectious agent is critical for appropriate treatment, of course. However, determining a patient’s genetic predisposition to infection would allow us to be more aggressive in our treatment of patients, whether we are speaking of vaccines or preventive drugs’, Awadalla says. EurekAlert

Scientists at the Montreal Neurological Institute and Hospital – The Neuro, McGill University working with a team at Oxford University have uncovered the genetic defect underlying a group of rare genetic disorders.
Using a new technique that has revolutionised genetic studies, the teams determined that mutations in the RMND1 gene were responsible for severe neurodegenerative disorders, in two infants, ultimately leading to their early death. Although the teams’ investigations dealt with an infant, their discovery also has implications for understanding the causes of later-onset neurological diseases.
The RMND1 gene encodes a protein that is an important component of the machinery in mitochondria which generates the chemical energy that all cells need to function. Mutations in genes affecting mitochondrial function are common causes of neurological and neuromuscular disorders in adults and children. It is estimated that one newborn baby out of 5000 is at risk for developing one of these disorders. Mortality among such cases is very high.
‘Mitochondria are becoming a focus of research because it’s clear they’re involved in neurodegenerative disorders in a fairly big way,’ says Dr. Eric Shoubridge, an internationally recognised specialist on mitochondrial diseases at The Neuro and lead author of the paper published.
‘For instance, we’re finding that dysfunctional mitochondria may be at the heart of adult-onset disorders like Parkinson’s and Alzheimer’s disease.’
Discovery of the mutations in the RMND1 gene involved using whole-exome sequencing at the McGill University and Genome Québec Innovation Centre. This technique allows all of the genes in the body that code for proteins to be sequenced and analysed in a single experiment. At a cost of about $1000, whole-exome sequencing is much more economical than previous techniques in which lists of candidate genes had to be screened in the search for mutations. The technique is poised to change the face of genetic diagnosis, making testing more efficient and available.
‘Parents who have had a child with a mitochondrial disorder and who are hesitating to have another child now have the possibility to know the cause of the disease. With genetic information, they have reproductive options like in vitro fertilisation,’ says Dr. Shoubridge. The discovery of the RMND1 gene’s role sheds light on disorders of mitochondrial energy metabolism, but therapies to alleviate or cure such disorders remain elusive. Dr. Shoubridge is hopeful that the discovery will encourage pharmaceutical interest. ‘Drug companies are starting to be interested in rare diseases and metabolic disorders like this. They’re picking some genes as potential drug candidates.’ EurekAlert

The adverse side effects of certain hepatitis C medications can now be replicated and observed in Petri dishes and test tubes, thanks to a research team led by Craig Cameron, the Paul Berg Professor of Biochemistry and Molecular Biology at Penn State University. ‘The new method not only will help us to understand the recent failures of hepatitis C antiviral drugs in some patients in clinical trials,’ said Cameron. ‘It also could help to identify medications that eliminate all adverse effects.’ The team’s findings may help pave the way toward the development of safer and more-effective treatments for hepatitis C, as well as other pathogens such as SARS and West Nile virus.
First author Jamie Arnold, a research associate in Cameron’s lab at Penn State, explained that the hepatitis C virus (HCV), which affects over 170,000,000 people worldwide, is the leading cause of liver disease and, although antiviral treatments are effective in many patients, they cause serious side effects in others. ‘Many antiviral medications for treating HCV are chemical analogs for the building blocks of RNA that are used to assemble new copies of the virus’s genome, enabling it to replicate,’ he said. ‘These medications are close enough to the virus’s natural building blocks that they get incorporated into the virus’s genome. But they also are different in ways that lead to the virus’s incomplete replication. The problem, however, is that the medication not only mimics the virus’s genetic material, but also the genetic material of the patient. So, while the drug causes damage to the virus, it also may affect the patient’s own healthy tissues.’
A method to reveal these adverse side effects in the safety of a laboratory setting, rather than in clinical trials where patients may be placed at risk, has been developed by the research team, which includes Cameron; Arnold; Suresh Sharma, a research associate in Cameron’s lab; other scientists at Penn State; and researchers from other academic, government, and corporate labs. ‘We have taken anti-HCV medications and, in Petri dishes and test tubes, we have shown that these drugs affect functions within a cell’s mitochondria,’ Cameron explained. ‘The cellular mitochondria — a tiny structure known as ‘the powerhouse of the cell’ that is responsible for making energy known as ATP — is affected by these compounds and is likely a major reason why we see adverse effects.’ Cameron noted that scientists have known for some time that certain individuals have ‘sick’ mitochondria. Such individuals are likely more sensitive to the mitochondrial side effects of antiviral drugs.
‘We know that antiviral drugs, including the ones used to treat HCV, affect even normal, healthy mitochondria by slowing ATP output,’ Arnold added. ‘While a person with normal mitochondria will experience some ATP and mitochondrial effects, a person who is already predisposed to mitochondrial dysfunction will be pushed over the ‘not enough cellular energy’ threshold by the antiviral drug. The person’s mitochondria simply won’t be able to keep up.’
One of the problems with clinical trials, Arnold explained, is that a drug may be shown to be quite effective but, if even a miniscule percentage of patients have side effects, the U.S. Food and Drug Administration is obligated to put the trial on hold or stop the trial altogether. This possibility makes drug companies reluctant to invest money in drug trials after an adverse event has been observed, even when the drugs could still help millions of people. The researchers hope that their methods eventually will become a part of the pre-clinical development process for this class of antiviral drugs. ‘If we can show, in the lab, that a drug will cause side effects, then these compounds will not enter lengthy, expensive clinical trials and cause harm to patients ‘ he said. ‘What’s more, a drug company can invest its money more wisely and carefully in drug research that will produce safe and effective products. Better and more-willing investments by drug companies ultimately will help patients, because resources will be spent developing drugs that not only work, but that are safe for all patients.’ Penn State Univeristy

Testing asthmatic children for a specific gene could prevent their condition worsening, according to new research by scientists in Brighton and Dundee.
The arginine-16 genotype of the beta-2 receptor is carried by one in seven sufferers and the research found their condition could be aggravated by the use of the long-term controller medicine, Salmeterol, a long acting beta-receptor stimulant, which is administered through an inhaler.
Testing children for the genotype would identify those who might react poorly to Salmeterol and means their asthma control may improve with the use of alternative medicines.
The research was carried out by – Professor Somnath Mukhopadhyay from the Brighton and Sussex Medical School (BSMS) which is run jointly by Brighton and Sussex universities, and Professor Brian Lipworth and genetics expert Professor Colin Palmer, both from the University of Dundee.
They carried out the first genotyped study comparing additional treatments given to asthmatic children who continue to experience symptoms despite use of their prescribed inhaled steroid preventer.
More than a million UK children have asthma and over 150,000 are affected by this genetic change, making them less likely to respond to Salmeterol. The researchers tested 62 children with the susceptible arginine-16 genotype. They had all missed school or had treatment at hospital or out-of-hours GP surgeries as a result of their asthma, despite being treated with regular inhaled steroids.
While continuing with their usual preventer, the children were randomly assigned to two treatment groups for the period of a year – Montelukast or Salmeterol.
The research found they responded better to an alternative anti-inflammatory medicine, Montelukast. They experienced an improved quality of life, wheezed and coughed much less, and were less likely to experience worsening of their symptoms and needing more ‘reliever’ treatment, compared to the Salmeterol users.
At the start of the research, 36 per cent of these children tested needed to use their relievers every day. But by the end of the year-long study, the number of children needing daily reliever use had halved in the group using Montelukast. In contrast, there was no improvement for the children in the Salmeterol group. This is despite the fact that Salmeterol is currently the preferred drug for children with asthma who are not controlled with inhaled steroids.
The researchers have warned that many children with serious asthma respond poorly to Salmeterol and may be suffering needlessly from asthma, regularly missing out on sports and recording low school attendances during long-term treatment with this medicine. They said their treatment may be made more effective with the help of a simple relatively inexpensive gene test. Brighton and Sussex Medical School

Researchers from the Guy Rouleau Laboratory affiliated with the CHUM Research Centre and the CHU–Sainte-Justine Research Centre have discovered the genetic cause of a rare disease reported only in patients originating from Newfoundland: hereditary spastic ataxia (HSA).
This condition is characterised by lower-limb spasticity (or stiffness) and ataxia (lack of co-ordination), the latter leading to speech and swallowing problems, and eye movement abnormalities. The disease is not deadly, but people start developing gait problems between 10 to 20 years of age, walk with a cane in their 30s, and in the most severe cases, are wheel-chair bound in their 50s. It has been shown that HSA is transmitted from the affected parent to the child in a dominant fashion, which means there is a 50% chance of the child having the mutation.
Researchers and clinicians from Memorial University (St. John’s, Newfoundland) contacted Dr. Rouleau, who is also a professor of medicine at the University of Montreal, over a decade ago to investigate the genetics behind this disorder occurring in three large Newfoundland families. Dr. Inge Meijer, a former doctoral candidate in the Rouleau Laboratory, discovered that these families were ancestrally related, and in 2002, identified the locus (DNA region) containing the mutation causing HSA.
A few years later, Cynthia Bourassa, lead author of the study, took over Meijer’s project. ‘I re-examined some unresolved details using newer and more advanced methods,’ explains Bourassa, who is a master’s student in the Faculty of Medicine at the University of Montreal. She then teamed up with Dr. Nancy Merner, who after obtaining her Ph.D. at Memorial University moved to Montreal to further her career in genetic research. ‘It is an honour to be a part of this study and impact the lives of my fellow Newfoundlanders. I knew coming into the Rouleau Laboratory that the genetic factors of the HAS families had not yet been identified. In fact, I asked about them on my first day of work, shortly after which I teamed up with Cynthia and we found the gene!’
The gene harbouring the mutation is VAMP1, encoding the synaptobrevin protein. ‘Not only was the mutation present in all patients and absent from all population controls, but also, synaptobrevin is a key player in neurotransmitter release, which made sense at the functional level as well,’ says Bourassa. In fact, the authors believe that this mutation in the VAMP1 gene may affect neurotransmission in areas of the nervous system where the synaptobrevin protein is located, causing the unique symptoms of HSA. In other words, there are not enough messengers released, so nerves cannot function optimally.
‘The discovery will benefit the families affected with this extremely debilitating disorder,’ says Dr. Rouleau. ‘A genetic diagnostic test can be developed, and genetic counselling can be provided to family members who are at risk of developing the disease or having children with the condition.’ University of Montreal