Scientists from the Keck School of Medicine of USC have discovered the first gene associated with autism that has genome-wide significance. The discovery may allow researchers to more effectively study the causes of autism and develop new treatments for the disorder.
‘Our study shows that a highly significant genetic signal for autism pointed to a new gene, MSNP1AS,’ said Daniel B. Campbell, the study’s senior author and assistant professor of psychiatry and the behavioural sciences at the Keck School.
‘MSNP1AS is a non-coding RNA, which means it does not code for a protein. More than half of the RNAs made in the human brain are non-coding, but their functions are often unknown,’ he explained. ‘We found that expression of MSNP1AS is increased 12-fold in the brains of people with autism and discovered that it controls expression of a protein called moesin, which influences brain development and immune response. The discovery of a functional non-coding RNA opens new avenues of investigation for autism.’
Autism spectrum disorder (ASD) is a lifelong neuro-developmental disability characterised by problems with social interaction, communication and repetitive behaviours. The Centers for Disease Control and Prevention estimates that one in 88 children in the United States have an ASD.
ASD is highly heritable, suggesting that genetics are an important contributing factor, but many questions about its causes remain. There currently is no cure for the disorder.
A 2009 study published in Nature by Kai Wang, now assistant professor of psychiatry and preventive medicine at the Keck School, found a significant association of genetic risk factors underlying ASD with genetic markers on chromosome 5. The nearest genes (CDH9 and CDH10), however, were more than 1 million base pairs from the marker – too far to explain the link to autism.
Campbell and his team at the Keck School’s Zilkha Neurogenetic Institute hypothesised that a previously undetected genetic component might lie closer to the markers. Using bioinformatics techniques, they discovered that a new gene, MSNP1AS, was located directly at the autism-associated genetic markers. They also found that expression levels of the gene were higher in brain samples from autism patients than in samples from healthy individuals. They also demonstrated that overexpression of MSNP1AS caused a decrease in moesin protein.
‘The autism genetic signal gave us a treasure map with a big X over the Mojave Desert,’ Campbell said. ‘Instead of searching in the bright lights of Las Vegas or Los Angeles, the nearest big cities, we decided to search right under the big X on the map. We discovered the treasure [MSNP1AS] in the desert, just where the map said it was. And, once we found the treasure, we realised that it was a key to a mansion in Paris – that MSNP1AS regulates expression of moesin, a protein that is generated by a gene on the X chromosome [a different continent] and is known to impact both brain development and immune response.’
Previous studies showed that moesin RNA was central to a network of genes with altered expression in postmortem brain samples from people with autism. Like the previous studies, Campbell and his colleagues found that moesin RNA levels were increased in those brain samples, while actual moesin protein levels were not.
‘This suggests that MSNP1AS RNA may play a role in suppressing moesin protein expression, which may increase the risk for autism,’ said Tara Kerin, the study’s lead author and a Ph.D. candidate in preventive medicine at the Keck School.
While their results hinted that both MSNP1AS and moesin potentially could be targets for therapy, there is simply too much information that remains a mystery.
‘This is just a first step,’ Kerin said. ‘It’s just another clue that may help unlock the puzzle that we have before us.’
Keck School of Medicine
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One in eight women will be diagnosed with breast cancer during her lifetime. The earlier cancer is detected, the better the chance of successful treatment and long-term survival. However, early cancer diagnosis is still challenging as testing by mammography remains cumbersome, costly, and in many cases, cancer can only be detected at an advanced stage. A team based in the Dept. of Biomedical Engineering at McGill University’s Faculty of Medicine has developed a new microfluidics-based microarray that could one day radically change how and when cancer is diagnosed.
For years, scientists have worked to develop blood tests for cancer based on the presence of the Carcinoembryonic Antigen (CEA), a protein biomarker for cancer identified over 40 years ago by McGill’s Dr. Phil Gold. This biomarker, however, is also found in healthy people and its concentration varies from person to person depending on genetic background and lifestyle. As such, it has not been possible to establish a precise cut-off between healthy individuals and those with cancer.
‘Attempts have been made to overcome this problem of person-to-person variability by seeking to establish a molecular ‘portrait’ of a person by measuring both the concentration of multiple proteins in the blood and identifying the signature molecules that, taken together, constitute a characteristic ‘fingerprint’ of cancer,’ explains Dr. David Juncker, the team’s principal investigator. ‘However, no reliable set of biomarkers has been found, and no such test is available today. Our goal is to find a way around this.’
Dr. Mateu Pla-Roca, the study’s first author, along with members of Juncker’s team, began by analysing the most commonly used existing technologies that measure multiple proteins in the blood and developing a model describing their vulnerabilities and limitations. Specifically, they discovered why the number of protein targets that can be measured simultaneously has been limited and why the accuracy and reproducibility of these tests have been so challenging to improve. Armed with a better understanding of these limitations, the team then developed a novel microfluidics-based microarray technology that circumvents these restrictions. Using this new approach, it then became possible to measure as many protein biomarkers as desired while minimising the possibility of obtaining false results.
Juncker’s biomedical engineering group, together with oncology and bioinformatics teams from McGill’s Goodman Cancer Research Centre, then measured the profile of 32 proteins in the blood of 11 healthy controls and 17 individuals who had a particular subtype of breast cancer (oestrogen receptor-positive). The researchers found that a subset of six of these 32 proteins could be used to establish a fingerprint for this cancer and classify each of the patients and healthy controls as having or not having breast cancer.
‘While this study needs to be repeated with additional markers and a greater diversity of patients and cancer subsets before such a test can be applied to clinical diagnosis, these results nonetheless underscore the exciting potential of this new technology,’ said Juncker.
Looking ahead, Juncker and his collaborators have set as their goal the development of a simple test that can be carried out in a physician’s office using a droplet of blood, thereby reducing dependence on mammography and minimizing attendant exposure to X-rays, discomfort and cost. His lab is currently developing a hand-held version of the test and is working on improving its sensitivity so as to be able to accurately detect breast cancer and ultimately, many other diseases, at the earliest possible stage.
McGill University
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Personalised prognostic tools and gene-based therapies may improve the survival and quality of life of patients suffering from glioblastoma, an aggressive and deadly form of brain cancer, reports a new University of Illinois study funded by the NIH National Cancer Institute.
‘We confirmed known biomarkers of glioblastoma survival and discovered new general and clinical-dependent gene profiles,’ said Nicola Serao, a U of I Ph.D. candidate in animal sciences with a focus in statistical genomics. ‘We were able to compare biomarkers across three glioblastoma phases that helped us gain insight into the roles of genes associated with cancer survival.’
Glioblastoma is a complex, multifactorial disease that has swift and devastating consequences, Serao said. Although some genes have been associated with the presence of glioblastoma, few have been identified as prognostic biomarkers of glioblastoma survival and fewer have been confirmed in independent reports.
‘You can’t just find one gene that is related to this cancer and fix it,’ he said. ‘This is one of the aspects of our research that makes it unique. We were able to look at several genes at the same time and relate our findings to this cancer.’
Using genomic information from more than 22,000 genes, Serao took this huge piece of information and began slicing away at it, one gene at a time, until he ended up with a group of genes related to brain cancer.
He studied different survival variables, including length of survival from birth to death, from diagnosis to death, and from diagnosis to progression of the cancer.
‘We studied different variables, but they were complementary, and allowed us to learn more about those genes,’ he said. ‘We understand that some genes have much more impact in cancer than others. And we also discovered that some genes only appeared in one variable, so they were specific for a given phase of cancer.’
This study not only evaluated genes influencing survival, but also took into consideration clinical factors such as age, race and gender.
‘Our research suggests you can’t treat all patients the same,’ Serao said. ‘For example, we found gene expression patterns that have different, and sometimes opposite, relationships with survival in males and females and concluded that treatments affecting these genes will not be equally effective. Personalised therapy dependent on gender, race and age is something that is possible today with our advanced genomic tools.’
Recognising that genes seldom act alone, this team of researchers took several genes into consideration at the same time and uncovered networks of genes related to glioblastoma survival.
Sandra Rodriguez Zas, co-researcher and U of I professor of animal science and bioinformatics, said they looked at commonalities between the genes linked to glioblastoma survival and progression, too.
‘If a large number of genes linked to survival belong to a particular pathway, this pathway is considered enriched,’ Rodriguez Zas said. ‘Depending on whether the pathway and genes have tumour suppressor or oncogenic characteristics, we should be able to use that information to support or attack that pathway with targeted therapies.’
Gaining a deeper understanding of the biological meaning, or roles, for these genes will provide researchers with even more ammunition to fight this deadly form of brain cancer.
‘Because of the innovative approach we used, we believe we can more confidently predict whether a patient will have a shorter or longer survival rate and select the most adequate therapies,’ she said.
Illinois.
University of Illinois College of Agricultural, Consumer and Environmental Sciences
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Virginia Commonwealth University School of Medicine researchers have discovered that changes in the gene expression of a key enzyme may contribute to high blood pressure and increase susceptibility to forming blood clots in pregnant women with preeclampsia.
These findings could provide clues to the best treatment approaches for high blood pressure and the formation of blood clots that can block blood flow to a pregnant woman’s internal organs and lead to organ failure.
Researchers have been working to determine the root cause of preeclampsia on the molecular level and have now identified that epigenetic mechanisms may be at play. Epigenetics refers to changes in gene expression that are mediated through mechanisms other than changes in the DNA sequence.
In a study published, the VCU team reported that thromboxane synthase – an important inflammatory enzyme – is increased in the blood vessels of expectant mothers with preeclampsia. The thromboxane synthase gene codes for this enzyme, which is involved in several processes including cardiovascular disease and stroke. This enzyme results in the synthesis of thromboxane, which increases blood pressure and causes blood clots.
‘The present work is unique because it opens up a new concept as to the cause and subsequent consequences of preeclampsia relating to epigenetics,’ said corresponding author Scott W. Walsh, Ph.D., professor in the VCU Department of Obstetrics and Gynecology. ‘It is the first study to show that epigenetic alterations in the blood vessels of the mother are related to preeclampsia.’
According to Walsh, one of the main epigenetic mechanisms is methylation of the DNA, which controls the expression of genes. The increase of this enzyme in the blood vessels is related to reduced DNA methylation and the infiltration of neutrophils into the blood vessels. Neutrophils are white blood cells that normally help fight infection.
In the future, Walsh said some potential treatments for preeclampsia may include inhibition of thromboxane synthase, blockade of thromboxane receptors or dietary supplementation with folate. He said that folate supplementation could increase methylation donors to protect against adverse changes in DNA methylation that affect expression of the thromboxane synthase enzyme.
Virginia Commonwealth University
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A DNA repair pathway-focused score has the potential to help determine if first-line platinum based chemotherapy can benefit advanced-stage ovarian cancer patients, according to a study.
Most ovarian cancer patients are diagnosed with advanced disease (stages III and IV). They undergo surgery to remove as much tumour as possible, and then undergo platinum-based chemotherapy. But tools to predict response to platinum-based chemotherapy in ovarian cancer patients have been inadequate.
In order to determine if a DNA repair pathway-focused score could help predict outcomes for ovarian cancer patients treated with platinum-based chemotherapy, Josephine Kang, M.D., Ph.D., of the Department of Radiation Oncology at Dana Farber Cancer Institute, and colleagues gathered gene expression data from The Cancer Genome Atlas (TCGA) database for patients with advanced stage ovarian cancer, and established a molecular score by looking at the genes involved in platinum-induced DNA damage repair pathways. The patients were placed either into low or high score categories, and the prognostic value of the score for overall survival, recurrence free survival, and progression-free survival was assessed.
The researchers found that patients with high scores showed a statistically significant improved overall survival compared to the patients with low scores. These patients’ score was positively correlated with complete response rate, recurrence-free survival, and progression-free survival. The researchers also found that the patients’ scores outperformed other known clinical factors in predicting overall survival in the TCGA dataset as well as in two additional validation sets. ‘Developing the ability to predict OS and outcomes to chemotherapy using prognostic markers such as the score is critical, particular in ovarian cancer, because there are presently no other good clinical measures to predict response to standard platinum-based chemotherapy,’ the authors write.
They also note the study’s limitations, namely that the score has not yet been tested prospectively in a clinical trial, although they do believe it is ready for testing. ‘With additional prospective validation in clinical trials, we hope that the score can become a powerful tool that is useful in stratifying advanced-stage ovarian cancer patients toward optimal treatments incorporating new treatment regimens vs. current standard of care,’ the authors write.
EurekAlert
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Scientists have identified which strains of the Toxoplasma gondii parasite, the cause of toxoplasmosis, are most strongly associated with premature births and severe birth defects in the United States. The researchers used a new blood test developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, to pinpoint T. gondii strains that children acquire from their acutely infected mothers while in the womb.
Pregnant women can become infected with T. gondii through contact with cat faeces that contain infectious forms of the parasite or by eating undercooked meat. Women who become infected while pregnant may miscarry, give birth prematurely, or have babies with eye or brain damage.
‘If undetected or untreated, congenital toxoplasmosis can have serious consequences for a child’s quality of life,’ noted NIAID Director Anthony S. Fauci, M.D. ‘The findings from this study support the value of screening for toxoplasmosis to identify patients who could benefit from treatment.’
Currently available blood tests can determine whether a person has ever been infected with any strain of Toxoplasma parasite. The experimental test developed at NIAID improves upon the older tests because it can detect the presence of strain-specific antibodies that distinguish infecting strains from one another. The test was developed by Michael Grigg, Ph.D., of NIAID’s Laboratory of Parasitic Diseases, and his colleagues. It was applied to blood samples collected between 1981 and 2009 as part of the National Collaborative Chicago-Based Congenital Toxoplasmosis Study. The study of congenitally infected children was initiated by NIAID grantee Rima McLeod, M.D., of the University of Chicago, who is the first author of the new study.
At least 15 distinct T. gondii strain types have been found throughout the world. In France, where research has been done to establish which strains are most common, a strain called type II predominates. Type II parasites can be distinguished from all other strains, which are collectively termed not exclusively type II strains (or NE-II).
Using the new test, the researchers found evidence of either type II or NE-II infections in 183 of the mother-child pairs in the national congenital toxoplasmosis study. Statistical analysis revealed that NE-II parasites were more likely to be associated with premature birth, and infants infected with these strains were more likely to have severe manifestations of disease than infants infected by type II parasites. For example, severe eye damage was seen in 67 percent of NE-II cases (59 out of 88), while such eye damage was present in only 39 percent of type II cases (18 out of 46). The researchers noted, however, that the association is not absolute, and that mild, moderate or severe disease can result regardless of the infecting strain.
‘We knew that, in mice, certain parasite strains are clearly associated with severe disease,’ said Dr. Grigg. ‘But we didn’t know if the same association between strain type and disease severity would hold true for people. Until now, we had not systematically determined whether infected people in the United States had European-type strains or other types, and we also hadn’t determined whether strains found here would have more severe disease symptoms associated with them.’
When she helped start the congenital toxoplasmosis study in 1981, optimal drug treatment regimens were unknown, said Dr. McLeod. Now, thanks in part to controlled clinical trials run under the auspices of the study, the condition can be successfully treated and many babies who are diagnosed before or shortly after birth and who are treated suffer few or no ill effects. When the researchers looked at the clinical histories of those children in the long-term study who had been diagnosed with congenital toxoplasmosis during gestation and whose mothers had received drug treatment prior to giving birth, the association between NE-II and severe disease at birth vanished. ‘Our study demonstrates that outcomes are equally good following postnatal treatment for type II and NE-II parasites, although not all outcomes are favorable for all children,’ she said.
In France, all pregnant women are screened for Toxoplasma infection. Prompt treatment is offered to any woman who becomes infected while pregnant, thus lessening the chance that the parasite will damage the fetus, Dr. McLeod noted. ‘In the United States, obstetrical screening for Toxoplasma infection is rarely practiced. This new study underscores the value of identifying all patients who will benefit from treatment and suggests that widespread screening and treatment of pregnant women who are infected could prevent infants from suffering eye and brain damage due to congenital toxoplasmosis,’ she said.
EurekAlert
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Biomarkers which could help to predict resistance to chemotherapy in breast cancer patients have been identified by researchers from the University of Hull.
The researchers found a family of proteins to be twice as prevalent in clinical samples obtained from breast cancer patients who were resistant to chemotherapy than those who were successfully treated.
Chemotherapy resistance is a major problem for some types of breast cancer and many patients undergo treatment that does not work, delaying other more suitable treatments and subjecting the patient to adverse side effects in the process.
The Hull research identifies a number of potential biomarkers associated with resistance to common chemotherapy drugs, including epirubicin and docetaxel.
Lead researcher Dr Lynn Cawkwell, says: ‘A major goal in cancer research is to be able to predict the response of a patient to chemotherapy. Unfortunately, a reliable test has not yet been developed to achieve this. We hope our work can help to bring us a step closer.
‘Most of my work uses clinical samples instead of cell lines, thanks to the links I have with oncologists and surgeons at Castle Hill Hospital in Hull. Studying clinical samples gives a more accurate representation of what is relevant in real-life diseases.’
The project used two high-throughput processes to screen clinical samples of breast tumour tissue.
One screening method using antibodies identified 38 proteins that were twice as prevalent in samples from patients who were resistant to chemotherapy than those who were successfully treated. The other screening method used mass spectrometry and uncovered 57 potential biomarkers of which five belong to the 14-3-3 protein family.
The findings from both screening methods highlight the possible importance of proteins from the 14-3-3 family and their potential for development into a predictive test for clinical use. Dr Cawkwell’s team hope to investigate the protein family’s role more fully in chemotherapy resistance.
‘If we’re correct, we hope that by testing for these proteins, doctors will be able to anticipate a patient’s response to different chemotherapies, and decide which course of treatment is most appropriate for them.’
Dr Cawkwell’s team is continuing with this study, as well as investigating radiotherapy resistance in a number of different cancers.
University of Hull
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Researchers at the Hospital de Mar Research Institute (IMIM) have discovered that the protein LOXL2 has a function within the cell nucleus thus far unknown. They have also described a new chemical reaction of this protein on histone H3 that would be involved in gene silencing, one of which would be involved in the progression of breast, larynx, lung and skin tumours.
Led by Dr Sandra Peiró, the study is a significant advance in describing the evolution of tumours and opens the door to researching new treatments that block their activity. ‘LOXL2’s action on the intra-cellular level and its interaction with histone H3 stimulates tumour growth. The fact that the protein LOXL2 is an enzyme and is overly expressed in many types of cancer makes it a very good therapeutic target. Now that we know how it acts, we need to keep working to develop chemical inhibitors that counteract its activity’, the researcher explained.
Previous studies had identified the extra-cellular function of the protein LOXL2, and it was being studied as a possible therapeutic target for avoiding metastasis in certain kinds of tumours. However, this study has described the presence of this protein at the level of the cell nucleus for the first time.
The process of gene expression in cells consists of transforming the information of the DNA into the proteins necessary to carry out different functions. The DNA molecule has been found to form a certain structure due to its interaction with some proteins called histones. When these histones are modified, the structure of the DNA is also modified and the final result is the expression or non-expression of a certain group of genes.
In the case of tumour cells, the protein LOXL2 acts upon one of these histones (histone H3) and modifies it, eliminating the lysine 4 amino group, a change never described before. As a result of its action, the genes modulated by histone H3, modified by LOXL2, stop expression, preventing the cells from behaving normally and favouring tumour development.
The work of Sandra Peiró’s team is the conclusion of three years of effort focused on the biochemical characterisation of the protein LOXL2 and the study of its role in the modification of histone H3. Since this modification had never been described before, the data obtained open many lines of research. The location on the genomic level of the protein LOXL2 and histone H3, modified by LOXL2, and the possible existence of some enzyme that might neutralise its function, are two of the questions that the group aims to tackle in the years to come.
IMIM (Hospital del Mar Research Institute)
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The emotion and anxiety aroused by a single word – ‘cancer’ – spans ages, sexes, nations, races and classes.
But as we understand more about the disease, the idea that cancer is a single common enemy, is increasingly being challenged.
In late 2009, the publication of the first complete cancer genomes showed the extraordinary chaos present in the DNA inside cancer cells. But they also highlighted the molecular differences between different types of cancer – in this case, skin cancer and lung cancer
Other large gene studies have revealed even more differences between types of cancer, but have also increased out understanding of the differences between the ‘same’ cancer type in different people – the foundation of ‘personalised medicine’.
As this in-depth post on the Respectful Insolence blog describes, they found that no two women’s cancers were alike – there were differences across all the tumour samples. Even a subcategory like ‘triple-negative’ breast cancer doesn’t seem to be a single disease. And genetic differences also appeared between cells from the same tumour – known as ‘intratumour heterogeneity’.
This point was emphasised a few weeks earlier by researchers at our London Research Institute. They analysed multiple samples from the same patient’s kidney tumour and secondaries (where the cancer had spread to other parts of the body).
No two samples were identical, suggesting that there’s significant variation even inside a tumour. As we discussed in this blog post, it looks like tumours can be highly varied, creating new challenges in the search for personalised medicine.
Which brings us to today’s news, of a landmark Cancer Research UK-funded study.
Through intricate genetic analysis, the same British and Canadian researchers, led by Professor Carlos Caldas from our Cambridge Research Institute and Professor Sam Aparicio from the British Columbia Cancer Centre in Canada, have uncovered crucial new information about breast cancer.
Their study group, METABRIC (Molecular Taxonomy of Breast Cancer International Consortium), looked at the patterns of molecules inside tumours from nearly two thousand women, for whom information about the tumour characteristics had been meticulously recorded.
They compared this with the women’s survival, and other information, like their age at diagnosis.
While many other studies have highlighted differences between cancers, the METABRIC study looked at so many tumours that they could spot new patterns and ‘clusters’ in the data.
Their conclusion is that what we call ‘breast cancer’ is in fact at least ten different diseases, each with its own molecular fingerprint, and each with different weak spots.
This is simultaneously daunting and heartening – daunting because each of these diseases will likely need a different strategy to overcome it; and heartening because it opens up multiple new fronts in our efforts to beat breast cancer.
Cancer Reseach UK
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Researchers at National Jewish Health have discovered a novel genetic mechanism of immune deficiency. Magdalena M. Gorska, MD, PhD, and Rafeul Alam, MD, PhD, identified a mutation in Unc119 that causes immunodeficiency known as idiopathic CD4 lymphopenia. Unc119 is a signalling protein that activates and induces T cell proliferation. The mutation impairs Unc119 ability to activate T cells.
‘A better understanding of the molecular mechanisms associated with this mutation will improve diagnosis and pave the way for development of new therapies,’ said Dr. Gorska.
Nearly a decade ago Drs. Alam and Gorska identified Unc119 as a novel activator of SRC-type tyrosine kinases, important regulators of cellular function. Since then, they have published numerous papers where they characterised the function of this protein in various aspects of the immune system.
Idiopathic CD4 lymphopenia is a rare and heterogeneous syndrome defined by low levels of CD4 T cells in the absence of HIV infection, which predisposes patients to infections and malignancies. Recent research by others had linked the syndrome to reduced activation of the SRC-type kinase known as Lck. The latter kinase is involved in T cell development, activation and proliferation.
So, Drs. Alam and Gorska thought Unc119, an activator of Lck, might be involved. They kept an eye out for patients with CD4 lymphopenia coming to National Jewish Health, which specialises in immune-related disorders as well as respiratory and cardiac diseases. They identified three patients with CD4 lymphopenia, then sequenced their Unc119 gene as well as the Unc119 gene in several patients who suffered low CD4 T cell counts as a result of other conditions.
One of the three patients, a 32-year-old woman with a history of recurrent infections, had a missense mutation in her Unc119 gene. The same mutation was not present in other lymphopenia patients nor in any genetic database.
The researchers then performed several studies with the woman’s blood cells, to understand the mutation’s effect. They introduced the mutated gene into normal T cells and examined the outcome.
The mutation prevents Lck activation and its downstream signalling. It also reduces the amount of Lck found near the plasma membrane, where it plays a major role in propagating signals from the T-cell receptor. Proliferation of T cells, which normally occurs on stimulation of T-cell receptors, was profoundly reduced in cells from the patient.
‘Since we originally published our findings earlier this year, we have received inquiries from many physicians with lymphopenia subjects,’ said Dr. Alam. ‘Working with them, we expect to find several more patients with this novel mutation, which should help us better understand its effect, improve diagnosis and possibly find therapies.’
At this point there is no treatment for CD4 lymphopenia caused by this mutation other than close monitoring of the patient and treatment of resulting infections and malignancies.
National Jewish Health
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Scientists find unexpected new autism gene
, /in E-News /by 3wmediaScientists from the Keck School of Medicine of USC have discovered the first gene associated with autism that has genome-wide significance. The discovery may allow researchers to more effectively study the causes of autism and develop new treatments for the disorder.
‘Our study shows that a highly significant genetic signal for autism pointed to a new gene, MSNP1AS,’ said Daniel B. Campbell, the study’s senior author and assistant professor of psychiatry and the behavioural sciences at the Keck School.
‘MSNP1AS is a non-coding RNA, which means it does not code for a protein. More than half of the RNAs made in the human brain are non-coding, but their functions are often unknown,’ he explained. ‘We found that expression of MSNP1AS is increased 12-fold in the brains of people with autism and discovered that it controls expression of a protein called moesin, which influences brain development and immune response. The discovery of a functional non-coding RNA opens new avenues of investigation for autism.’
Autism spectrum disorder (ASD) is a lifelong neuro-developmental disability characterised by problems with social interaction, communication and repetitive behaviours. The Centers for Disease Control and Prevention estimates that one in 88 children in the United States have an ASD.
ASD is highly heritable, suggesting that genetics are an important contributing factor, but many questions about its causes remain. There currently is no cure for the disorder.
A 2009 study published in Nature by Kai Wang, now assistant professor of psychiatry and preventive medicine at the Keck School, found a significant association of genetic risk factors underlying ASD with genetic markers on chromosome 5. The nearest genes (CDH9 and CDH10), however, were more than 1 million base pairs from the marker – too far to explain the link to autism.
Campbell and his team at the Keck School’s Zilkha Neurogenetic Institute hypothesised that a previously undetected genetic component might lie closer to the markers. Using bioinformatics techniques, they discovered that a new gene, MSNP1AS, was located directly at the autism-associated genetic markers. They also found that expression levels of the gene were higher in brain samples from autism patients than in samples from healthy individuals. They also demonstrated that overexpression of MSNP1AS caused a decrease in moesin protein.
‘The autism genetic signal gave us a treasure map with a big X over the Mojave Desert,’ Campbell said. ‘Instead of searching in the bright lights of Las Vegas or Los Angeles, the nearest big cities, we decided to search right under the big X on the map. We discovered the treasure [MSNP1AS] in the desert, just where the map said it was. And, once we found the treasure, we realised that it was a key to a mansion in Paris – that MSNP1AS regulates expression of moesin, a protein that is generated by a gene on the X chromosome [a different continent] and is known to impact both brain development and immune response.’
Previous studies showed that moesin RNA was central to a network of genes with altered expression in postmortem brain samples from people with autism. Like the previous studies, Campbell and his colleagues found that moesin RNA levels were increased in those brain samples, while actual moesin protein levels were not.
‘This suggests that MSNP1AS RNA may play a role in suppressing moesin protein expression, which may increase the risk for autism,’ said Tara Kerin, the study’s lead author and a Ph.D. candidate in preventive medicine at the Keck School.
While their results hinted that both MSNP1AS and moesin potentially could be targets for therapy, there is simply too much information that remains a mystery.
‘This is just a first step,’ Kerin said. ‘It’s just another clue that may help unlock the puzzle that we have before us.’ Keck School of Medicine
Detecting breast cancer’s fingerprint in a droplet of blood
, /in E-News /by 3wmediaOne in eight women will be diagnosed with breast cancer during her lifetime. The earlier cancer is detected, the better the chance of successful treatment and long-term survival. However, early cancer diagnosis is still challenging as testing by mammography remains cumbersome, costly, and in many cases, cancer can only be detected at an advanced stage. A team based in the Dept. of Biomedical Engineering at McGill University’s Faculty of Medicine has developed a new microfluidics-based microarray that could one day radically change how and when cancer is diagnosed.
For years, scientists have worked to develop blood tests for cancer based on the presence of the Carcinoembryonic Antigen (CEA), a protein biomarker for cancer identified over 40 years ago by McGill’s Dr. Phil Gold. This biomarker, however, is also found in healthy people and its concentration varies from person to person depending on genetic background and lifestyle. As such, it has not been possible to establish a precise cut-off between healthy individuals and those with cancer.
‘Attempts have been made to overcome this problem of person-to-person variability by seeking to establish a molecular ‘portrait’ of a person by measuring both the concentration of multiple proteins in the blood and identifying the signature molecules that, taken together, constitute a characteristic ‘fingerprint’ of cancer,’ explains Dr. David Juncker, the team’s principal investigator. ‘However, no reliable set of biomarkers has been found, and no such test is available today. Our goal is to find a way around this.’
Dr. Mateu Pla-Roca, the study’s first author, along with members of Juncker’s team, began by analysing the most commonly used existing technologies that measure multiple proteins in the blood and developing a model describing their vulnerabilities and limitations. Specifically, they discovered why the number of protein targets that can be measured simultaneously has been limited and why the accuracy and reproducibility of these tests have been so challenging to improve. Armed with a better understanding of these limitations, the team then developed a novel microfluidics-based microarray technology that circumvents these restrictions. Using this new approach, it then became possible to measure as many protein biomarkers as desired while minimising the possibility of obtaining false results.
Juncker’s biomedical engineering group, together with oncology and bioinformatics teams from McGill’s Goodman Cancer Research Centre, then measured the profile of 32 proteins in the blood of 11 healthy controls and 17 individuals who had a particular subtype of breast cancer (oestrogen receptor-positive). The researchers found that a subset of six of these 32 proteins could be used to establish a fingerprint for this cancer and classify each of the patients and healthy controls as having or not having breast cancer.
‘While this study needs to be repeated with additional markers and a greater diversity of patients and cancer subsets before such a test can be applied to clinical diagnosis, these results nonetheless underscore the exciting potential of this new technology,’ said Juncker.
Looking ahead, Juncker and his collaborators have set as their goal the development of a simple test that can be carried out in a physician’s office using a droplet of blood, thereby reducing dependence on mammography and minimizing attendant exposure to X-rays, discomfort and cost. His lab is currently developing a hand-held version of the test and is working on improving its sensitivity so as to be able to accurately detect breast cancer and ultimately, many other diseases, at the earliest possible stage. McGill University
Personalised gene therapies may increase survival in brain cancer patients
, /in E-News /by 3wmediaPersonalised prognostic tools and gene-based therapies may improve the survival and quality of life of patients suffering from glioblastoma, an aggressive and deadly form of brain cancer, reports a new University of Illinois study funded by the NIH National Cancer Institute.
‘We confirmed known biomarkers of glioblastoma survival and discovered new general and clinical-dependent gene profiles,’ said Nicola Serao, a U of I Ph.D. candidate in animal sciences with a focus in statistical genomics. ‘We were able to compare biomarkers across three glioblastoma phases that helped us gain insight into the roles of genes associated with cancer survival.’
Glioblastoma is a complex, multifactorial disease that has swift and devastating consequences, Serao said. Although some genes have been associated with the presence of glioblastoma, few have been identified as prognostic biomarkers of glioblastoma survival and fewer have been confirmed in independent reports.
‘You can’t just find one gene that is related to this cancer and fix it,’ he said. ‘This is one of the aspects of our research that makes it unique. We were able to look at several genes at the same time and relate our findings to this cancer.’
Using genomic information from more than 22,000 genes, Serao took this huge piece of information and began slicing away at it, one gene at a time, until he ended up with a group of genes related to brain cancer.
He studied different survival variables, including length of survival from birth to death, from diagnosis to death, and from diagnosis to progression of the cancer.
‘We studied different variables, but they were complementary, and allowed us to learn more about those genes,’ he said. ‘We understand that some genes have much more impact in cancer than others. And we also discovered that some genes only appeared in one variable, so they were specific for a given phase of cancer.’
This study not only evaluated genes influencing survival, but also took into consideration clinical factors such as age, race and gender.
‘Our research suggests you can’t treat all patients the same,’ Serao said. ‘For example, we found gene expression patterns that have different, and sometimes opposite, relationships with survival in males and females and concluded that treatments affecting these genes will not be equally effective. Personalised therapy dependent on gender, race and age is something that is possible today with our advanced genomic tools.’
Recognising that genes seldom act alone, this team of researchers took several genes into consideration at the same time and uncovered networks of genes related to glioblastoma survival.
Sandra Rodriguez Zas, co-researcher and U of I professor of animal science and bioinformatics, said they looked at commonalities between the genes linked to glioblastoma survival and progression, too.
‘If a large number of genes linked to survival belong to a particular pathway, this pathway is considered enriched,’ Rodriguez Zas said. ‘Depending on whether the pathway and genes have tumour suppressor or oncogenic characteristics, we should be able to use that information to support or attack that pathway with targeted therapies.’
Gaining a deeper understanding of the biological meaning, or roles, for these genes will provide researchers with even more ammunition to fight this deadly form of brain cancer.
‘Because of the innovative approach we used, we believe we can more confidently predict whether a patient will have a shorter or longer survival rate and select the most adequate therapies,’ she said.
Illinois. University of Illinois College of Agricultural, Consumer and Environmental Sciences
Changes in gene expression may help explain high blood pressure in pregnancy
, /in E-News /by 3wmediaVirginia Commonwealth University School of Medicine researchers have discovered that changes in the gene expression of a key enzyme may contribute to high blood pressure and increase susceptibility to forming blood clots in pregnant women with preeclampsia.
These findings could provide clues to the best treatment approaches for high blood pressure and the formation of blood clots that can block blood flow to a pregnant woman’s internal organs and lead to organ failure.
Researchers have been working to determine the root cause of preeclampsia on the molecular level and have now identified that epigenetic mechanisms may be at play. Epigenetics refers to changes in gene expression that are mediated through mechanisms other than changes in the DNA sequence.
In a study published, the VCU team reported that thromboxane synthase – an important inflammatory enzyme – is increased in the blood vessels of expectant mothers with preeclampsia. The thromboxane synthase gene codes for this enzyme, which is involved in several processes including cardiovascular disease and stroke. This enzyme results in the synthesis of thromboxane, which increases blood pressure and causes blood clots.
‘The present work is unique because it opens up a new concept as to the cause and subsequent consequences of preeclampsia relating to epigenetics,’ said corresponding author Scott W. Walsh, Ph.D., professor in the VCU Department of Obstetrics and Gynecology. ‘It is the first study to show that epigenetic alterations in the blood vessels of the mother are related to preeclampsia.’
According to Walsh, one of the main epigenetic mechanisms is methylation of the DNA, which controls the expression of genes. The increase of this enzyme in the blood vessels is related to reduced DNA methylation and the infiltration of neutrophils into the blood vessels. Neutrophils are white blood cells that normally help fight infection.
In the future, Walsh said some potential treatments for preeclampsia may include inhibition of thromboxane synthase, blockade of thromboxane receptors or dietary supplementation with folate. He said that folate supplementation could increase methylation donors to protect against adverse changes in DNA methylation that affect expression of the thromboxane synthase enzyme. Virginia Commonwealth University
DNA repair pathway score for predicting chemotherapy response in ovarian cancer patients
, /in E-News /by 3wmediaA DNA repair pathway-focused score has the potential to help determine if first-line platinum based chemotherapy can benefit advanced-stage ovarian cancer patients, according to a study.
Most ovarian cancer patients are diagnosed with advanced disease (stages III and IV). They undergo surgery to remove as much tumour as possible, and then undergo platinum-based chemotherapy. But tools to predict response to platinum-based chemotherapy in ovarian cancer patients have been inadequate.
In order to determine if a DNA repair pathway-focused score could help predict outcomes for ovarian cancer patients treated with platinum-based chemotherapy, Josephine Kang, M.D., Ph.D., of the Department of Radiation Oncology at Dana Farber Cancer Institute, and colleagues gathered gene expression data from The Cancer Genome Atlas (TCGA) database for patients with advanced stage ovarian cancer, and established a molecular score by looking at the genes involved in platinum-induced DNA damage repair pathways. The patients were placed either into low or high score categories, and the prognostic value of the score for overall survival, recurrence free survival, and progression-free survival was assessed.
The researchers found that patients with high scores showed a statistically significant improved overall survival compared to the patients with low scores. These patients’ score was positively correlated with complete response rate, recurrence-free survival, and progression-free survival. The researchers also found that the patients’ scores outperformed other known clinical factors in predicting overall survival in the TCGA dataset as well as in two additional validation sets. ‘Developing the ability to predict OS and outcomes to chemotherapy using prognostic markers such as the score is critical, particular in ovarian cancer, because there are presently no other good clinical measures to predict response to standard platinum-based chemotherapy,’ the authors write.
They also note the study’s limitations, namely that the score has not yet been tested prospectively in a clinical trial, although they do believe it is ready for testing. ‘With additional prospective validation in clinical trials, we hope that the score can become a powerful tool that is useful in stratifying advanced-stage ovarian cancer patients toward optimal treatments incorporating new treatment regimens vs. current standard of care,’ the authors write. EurekAlert
Test links strains of common parasite to severe illness in US newborns
, /in E-News /by 3wmediaScientists have identified which strains of the Toxoplasma gondii parasite, the cause of toxoplasmosis, are most strongly associated with premature births and severe birth defects in the United States. The researchers used a new blood test developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, to pinpoint T. gondii strains that children acquire from their acutely infected mothers while in the womb.
Pregnant women can become infected with T. gondii through contact with cat faeces that contain infectious forms of the parasite or by eating undercooked meat. Women who become infected while pregnant may miscarry, give birth prematurely, or have babies with eye or brain damage.
‘If undetected or untreated, congenital toxoplasmosis can have serious consequences for a child’s quality of life,’ noted NIAID Director Anthony S. Fauci, M.D. ‘The findings from this study support the value of screening for toxoplasmosis to identify patients who could benefit from treatment.’
Currently available blood tests can determine whether a person has ever been infected with any strain of Toxoplasma parasite. The experimental test developed at NIAID improves upon the older tests because it can detect the presence of strain-specific antibodies that distinguish infecting strains from one another. The test was developed by Michael Grigg, Ph.D., of NIAID’s Laboratory of Parasitic Diseases, and his colleagues. It was applied to blood samples collected between 1981 and 2009 as part of the National Collaborative Chicago-Based Congenital Toxoplasmosis Study. The study of congenitally infected children was initiated by NIAID grantee Rima McLeod, M.D., of the University of Chicago, who is the first author of the new study.
At least 15 distinct T. gondii strain types have been found throughout the world. In France, where research has been done to establish which strains are most common, a strain called type II predominates. Type II parasites can be distinguished from all other strains, which are collectively termed not exclusively type II strains (or NE-II).
Using the new test, the researchers found evidence of either type II or NE-II infections in 183 of the mother-child pairs in the national congenital toxoplasmosis study. Statistical analysis revealed that NE-II parasites were more likely to be associated with premature birth, and infants infected with these strains were more likely to have severe manifestations of disease than infants infected by type II parasites. For example, severe eye damage was seen in 67 percent of NE-II cases (59 out of 88), while such eye damage was present in only 39 percent of type II cases (18 out of 46). The researchers noted, however, that the association is not absolute, and that mild, moderate or severe disease can result regardless of the infecting strain.
‘We knew that, in mice, certain parasite strains are clearly associated with severe disease,’ said Dr. Grigg. ‘But we didn’t know if the same association between strain type and disease severity would hold true for people. Until now, we had not systematically determined whether infected people in the United States had European-type strains or other types, and we also hadn’t determined whether strains found here would have more severe disease symptoms associated with them.’
When she helped start the congenital toxoplasmosis study in 1981, optimal drug treatment regimens were unknown, said Dr. McLeod. Now, thanks in part to controlled clinical trials run under the auspices of the study, the condition can be successfully treated and many babies who are diagnosed before or shortly after birth and who are treated suffer few or no ill effects. When the researchers looked at the clinical histories of those children in the long-term study who had been diagnosed with congenital toxoplasmosis during gestation and whose mothers had received drug treatment prior to giving birth, the association between NE-II and severe disease at birth vanished. ‘Our study demonstrates that outcomes are equally good following postnatal treatment for type II and NE-II parasites, although not all outcomes are favorable for all children,’ she said.
In France, all pregnant women are screened for Toxoplasma infection. Prompt treatment is offered to any woman who becomes infected while pregnant, thus lessening the chance that the parasite will damage the fetus, Dr. McLeod noted. ‘In the United States, obstetrical screening for Toxoplasma infection is rarely practiced. This new study underscores the value of identifying all patients who will benefit from treatment and suggests that widespread screening and treatment of pregnant women who are infected could prevent infants from suffering eye and brain damage due to congenital toxoplasmosis,’ she said. EurekAlert
Helping to improve the treatment of breast cancer
, /in E-News /by 3wmediaBiomarkers which could help to predict resistance to chemotherapy in breast cancer patients have been identified by researchers from the University of Hull.
The researchers found a family of proteins to be twice as prevalent in clinical samples obtained from breast cancer patients who were resistant to chemotherapy than those who were successfully treated.
Chemotherapy resistance is a major problem for some types of breast cancer and many patients undergo treatment that does not work, delaying other more suitable treatments and subjecting the patient to adverse side effects in the process.
The Hull research identifies a number of potential biomarkers associated with resistance to common chemotherapy drugs, including epirubicin and docetaxel.
Lead researcher Dr Lynn Cawkwell, says: ‘A major goal in cancer research is to be able to predict the response of a patient to chemotherapy. Unfortunately, a reliable test has not yet been developed to achieve this. We hope our work can help to bring us a step closer.
‘Most of my work uses clinical samples instead of cell lines, thanks to the links I have with oncologists and surgeons at Castle Hill Hospital in Hull. Studying clinical samples gives a more accurate representation of what is relevant in real-life diseases.’
The project used two high-throughput processes to screen clinical samples of breast tumour tissue.
One screening method using antibodies identified 38 proteins that were twice as prevalent in samples from patients who were resistant to chemotherapy than those who were successfully treated. The other screening method used mass spectrometry and uncovered 57 potential biomarkers of which five belong to the 14-3-3 protein family.
The findings from both screening methods highlight the possible importance of proteins from the 14-3-3 family and their potential for development into a predictive test for clinical use. Dr Cawkwell’s team hope to investigate the protein family’s role more fully in chemotherapy resistance.
‘If we’re correct, we hope that by testing for these proteins, doctors will be able to anticipate a patient’s response to different chemotherapies, and decide which course of treatment is most appropriate for them.’
Dr Cawkwell’s team is continuing with this study, as well as investigating radiotherapy resistance in a number of different cancers. University of Hull
New advances in the understanding of cancer progression
, /in E-News /by 3wmediaResearchers at the Hospital de Mar Research Institute (IMIM) have discovered that the protein LOXL2 has a function within the cell nucleus thus far unknown. They have also described a new chemical reaction of this protein on histone H3 that would be involved in gene silencing, one of which would be involved in the progression of breast, larynx, lung and skin tumours.
Led by Dr Sandra Peiró, the study is a significant advance in describing the evolution of tumours and opens the door to researching new treatments that block their activity. ‘LOXL2’s action on the intra-cellular level and its interaction with histone H3 stimulates tumour growth. The fact that the protein LOXL2 is an enzyme and is overly expressed in many types of cancer makes it a very good therapeutic target. Now that we know how it acts, we need to keep working to develop chemical inhibitors that counteract its activity’, the researcher explained.
Previous studies had identified the extra-cellular function of the protein LOXL2, and it was being studied as a possible therapeutic target for avoiding metastasis in certain kinds of tumours. However, this study has described the presence of this protein at the level of the cell nucleus for the first time.
The process of gene expression in cells consists of transforming the information of the DNA into the proteins necessary to carry out different functions. The DNA molecule has been found to form a certain structure due to its interaction with some proteins called histones. When these histones are modified, the structure of the DNA is also modified and the final result is the expression or non-expression of a certain group of genes.
In the case of tumour cells, the protein LOXL2 acts upon one of these histones (histone H3) and modifies it, eliminating the lysine 4 amino group, a change never described before. As a result of its action, the genes modulated by histone H3, modified by LOXL2, stop expression, preventing the cells from behaving normally and favouring tumour development.
The work of Sandra Peiró’s team is the conclusion of three years of effort focused on the biochemical characterisation of the protein LOXL2 and the study of its role in the modification of histone H3. Since this modification had never been described before, the data obtained open many lines of research. The location on the genomic level of the protein LOXL2 and histone H3, modified by LOXL2, and the possible existence of some enzyme that might neutralise its function, are two of the questions that the group aims to tackle in the years to come. IMIM (Hospital del Mar Research Institute)
Increasing the resolution on breast cancer
, /in E-News /by 3wmediaThe emotion and anxiety aroused by a single word – ‘cancer’ – spans ages, sexes, nations, races and classes.
But as we understand more about the disease, the idea that cancer is a single common enemy, is increasingly being challenged.
In late 2009, the publication of the first complete cancer genomes showed the extraordinary chaos present in the DNA inside cancer cells. But they also highlighted the molecular differences between different types of cancer – in this case, skin cancer and lung cancer
Other large gene studies have revealed even more differences between types of cancer, but have also increased out understanding of the differences between the ‘same’ cancer type in different people – the foundation of ‘personalised medicine’.
As this in-depth post on the Respectful Insolence blog describes, they found that no two women’s cancers were alike – there were differences across all the tumour samples. Even a subcategory like ‘triple-negative’ breast cancer doesn’t seem to be a single disease. And genetic differences also appeared between cells from the same tumour – known as ‘intratumour heterogeneity’.
This point was emphasised a few weeks earlier by researchers at our London Research Institute. They analysed multiple samples from the same patient’s kidney tumour and secondaries (where the cancer had spread to other parts of the body).
No two samples were identical, suggesting that there’s significant variation even inside a tumour. As we discussed in this blog post, it looks like tumours can be highly varied, creating new challenges in the search for personalised medicine.
Which brings us to today’s news, of a landmark Cancer Research UK-funded study.
Through intricate genetic analysis, the same British and Canadian researchers, led by Professor Carlos Caldas from our Cambridge Research Institute and Professor Sam Aparicio from the British Columbia Cancer Centre in Canada, have uncovered crucial new information about breast cancer.
Their study group, METABRIC (Molecular Taxonomy of Breast Cancer International Consortium), looked at the patterns of molecules inside tumours from nearly two thousand women, for whom information about the tumour characteristics had been meticulously recorded.
They compared this with the women’s survival, and other information, like their age at diagnosis.
While many other studies have highlighted differences between cancers, the METABRIC study looked at so many tumours that they could spot new patterns and ‘clusters’ in the data.
Their conclusion is that what we call ‘breast cancer’ is in fact at least ten different diseases, each with its own molecular fingerprint, and each with different weak spots.
This is simultaneously daunting and heartening – daunting because each of these diseases will likely need a different strategy to overcome it; and heartening because it opens up multiple new fronts in our efforts to beat breast cancer. Cancer Reseach UK
New genetic mechanism of immune deficiency discovered
, /in E-News /by 3wmediaResearchers at National Jewish Health have discovered a novel genetic mechanism of immune deficiency. Magdalena M. Gorska, MD, PhD, and Rafeul Alam, MD, PhD, identified a mutation in Unc119 that causes immunodeficiency known as idiopathic CD4 lymphopenia. Unc119 is a signalling protein that activates and induces T cell proliferation. The mutation impairs Unc119 ability to activate T cells.
‘A better understanding of the molecular mechanisms associated with this mutation will improve diagnosis and pave the way for development of new therapies,’ said Dr. Gorska.
Nearly a decade ago Drs. Alam and Gorska identified Unc119 as a novel activator of SRC-type tyrosine kinases, important regulators of cellular function. Since then, they have published numerous papers where they characterised the function of this protein in various aspects of the immune system.
Idiopathic CD4 lymphopenia is a rare and heterogeneous syndrome defined by low levels of CD4 T cells in the absence of HIV infection, which predisposes patients to infections and malignancies. Recent research by others had linked the syndrome to reduced activation of the SRC-type kinase known as Lck. The latter kinase is involved in T cell development, activation and proliferation.
So, Drs. Alam and Gorska thought Unc119, an activator of Lck, might be involved. They kept an eye out for patients with CD4 lymphopenia coming to National Jewish Health, which specialises in immune-related disorders as well as respiratory and cardiac diseases. They identified three patients with CD4 lymphopenia, then sequenced their Unc119 gene as well as the Unc119 gene in several patients who suffered low CD4 T cell counts as a result of other conditions.
One of the three patients, a 32-year-old woman with a history of recurrent infections, had a missense mutation in her Unc119 gene. The same mutation was not present in other lymphopenia patients nor in any genetic database.
The researchers then performed several studies with the woman’s blood cells, to understand the mutation’s effect. They introduced the mutated gene into normal T cells and examined the outcome.
The mutation prevents Lck activation and its downstream signalling. It also reduces the amount of Lck found near the plasma membrane, where it plays a major role in propagating signals from the T-cell receptor. Proliferation of T cells, which normally occurs on stimulation of T-cell receptors, was profoundly reduced in cells from the patient.
‘Since we originally published our findings earlier this year, we have received inquiries from many physicians with lymphopenia subjects,’ said Dr. Alam. ‘Working with them, we expect to find several more patients with this novel mutation, which should help us better understand its effect, improve diagnosis and possibly find therapies.’
At this point there is no treatment for CD4 lymphopenia caused by this mutation other than close monitoring of the patient and treatment of resulting infections and malignancies. National Jewish Health