Two new potential therapeutic targets for the treatment of pulmonary arterial hypertension, a deadly disease marked by high blood pressure in the lungs, have been identified by researchers at the University of Illinois at Chicago.
Early symptoms of pulmonary arterial hypertension include shortness of breath and exercise intolerance. As the disease progresses, patients may require oxygen supplementation and lung transplantation. Heart failure can develop and is a major cause of death in the disease.
Most cases of pulmonary hypertension are of unknown cause, though the condition often occurs in association with other diseases, including scleroderma, congenital heart disease and liver disease. One of the underlying factors driving the increased blood pressure in the lungs is a narrowing of the pulmonary blood vessels. This narrowing can be due to an abnormal proliferation of cells within the walls of the blood vessels, particularly in the smooth muscle cells of the pulmonary artery.
Jiwang Chen, research assistant professor of critical care medicine, sleep and allergy in the UIC College of Medicine, and his colleagues investigated the molecular mechanisms behind the abnormal proliferation of smooth muscle cells in the pulmonary artery and discovered two ways that the proliferation could be suppressed.
They knew that an enzyme, sphingosine kinase 1, that produces a signalling molecule called sphingosine-1-phosphate (S1P), had been linked to the abnormal growth of cells in cancer, including lung cancer.
“The characteristic proliferation of cells that line the blood vessels in pulmonary hypertension is similar to the abnormal growth and reproduction of cells that form cancerous tumours,” says Chen. “We wanted to see if sphingosine kinase 1 and S1P were involved in the development of pulmonary arterial hypertension.”
Looking at samples of lung tissue from patients, Chen and colleagues found that patients with pulmonary arterial hypertension had significantly elevated levels of both the enzyme and the signalling molecule it produces. They found similarly elevated levels of both molecules in mouse and rat models of pulmonary hypertension.
Knockout mice lacking the gene for sphingosine kinase 1 were less likely than normal mice to develop pulmonary hypertension when exposed to the low-oxygen conditions used to induce the disease in the laboratory.
Drugs that either suppress production of sphingosine kinase 1 or block the signalling of S1P through its receptors on smooth muscle cells prevented mice from developing pulmonary hypertension in low-oxygen conditions.
The researchers also showed in mice that over-production of sphingosine kinase 1 and S1P promote the proliferation of pulmonary artery smooth muscle cells.
“Our results yield two new potential targets for the development of drugs to treat or prevent the progression of pulmonary arterial hypertension,” Chen said.
“By blocking the binding site for S1P or suppressing the production of S1P, like we did in our experimental rodent model, we can reduce the proliferation of pulmonary artery smooth muscle cells, which is a major contributor to pulmonary hypertension.”
University of Illinois at Chicago
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A genetic mutation caused by ultraviolet light is likely the driving force behind millions of human skin cancers, according to researchers at the Stanford University School of Medicine.
The mutation occurs in a gene called KNSTRN, which is involved in helping cells divide their DNA equally during cell division.
Genes that cause cancer when mutated are known as oncogenes. Although KNSTRN hasn’t been previously implicated as a cause of human cancers, the research suggests it may be one of the most commonly mutated oncogenes in the world.
“This previously unknown oncogene is activated by sunlight and drives the development of cutaneous squamous cell carcinomas,” said Paul Khavari, MD, PhD, the Carl J. Herzog Professor in Dermatology in the School of Medicine and chair of the Department of Dermatology. “Our research shows that skin cancers arise differently from other cancers, and that a single mutation can cause genomic catastrophe.”
Cutaneous squamous cell carcinoma is the second most common cancer in humans. More than 1 million new cases are diagnosed globally each year. The researchers found that a particular region of KNSTRN is mutated in about 20 percent of cutaneous squamous cell carcinomas and in about 5 percent of melanomas.
Lee and Khavari made the discovery while investigating the genetic causes of cutaneous squamous cell carcinoma. They compared the DNA sequences of genes from the tumour cells with those of normal skin and looked for mutations that occurred only in the tumours. They found 336 candidate genes for further study, including some familiar culprits. The top two most commonly mutated genes were CDKN2A and TP53, which were already known to be associated with squamous cell carcinoma.
The third most commonly mutated gene, KNSTRN, was a surprise. It encodes a protein that helps to form the kinetochore — a structure that serves as a kind of handle used to pull pairs of newly replicated chromosomes to either end of the cell during cell division. Sequestering the DNA at either end of the cell allows the cell to split along the middle to form two daughter cells, each with the proper complement of chromosomes.
If the chromosomes don’t separate correctly, the daughter cells will have abnormal amounts of DNA. These cells with extra or missing chromosomes are known as aneuploid, and they are often severely dysfunctional. They tend to misread cellular cues and to behave erratically. Aneuploidy is a critical early step toward the development of many types of cancer.
The mutation in the KNSTRN gene was caused by the replacement of a single nucleotide, called a cytosine, with another, called a thymine, within a specific, short stretch of DNA. The swap is indicative of a cell’s attempt to repair damage from high-energy ultraviolet rays, such as those found in sunlight.
“Mutations at this UV hotspot are not found in any of the other cancers we investigated,” said Khavari. “They occur only in skin cancers.”
The researchers found the UV-induced KNSTRN mutation in about 20 percent of actinic keratoses — a premalignant skin condition that often progresses to squamous cell carcinoma — but never in 122 samples of normal skin, indicating the mutation is likely to be an early event in the development of squamous cell carcinomas.
Furthermore, overexpression of mutant KNSTRN in laboratory-grown human skin cells disrupted their ability to segregate their DNA during cell division and enhanced the growth of cancer cells in a mouse model of squamous cell carcinoma.
Finally, Lee compared five patient-derived squamous cell carcinomas that had the KNSTRN mutation with five samples that did not have the mutation. Although both sets of cells were aneuploid, those with the mutation had the most severely abnormal genomes.
Stanford University School of Medicine
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Researchers from Oregon State Public Health Lab have modified the protocol for a relatively new test for a dangerous form of antibiotic resistance, increasing its specificity to 100 percent. Their research, confirming the reliability of a test that can provide results in hours and is simple and inexpensive enough to be conducted in practically any clinical laboratory.
The test, called Carba NP, originally developed by Patrice Nordmann and Laurent Poirel at the University of Fribourg, Switzerland, and Laurent Dortet of the University Hospital of the South-Paris Medical School, France, allows for rapid identification of carbapenem-resistant Enterobacteriaceae (CRE), often referred to in the media as ‘super bugs’ for their ability to resist most major antibiotics. Carbapenems are an important class of powerful antibiotics for treating severe infections caused by multidrug-resistant Gram negative bacteria. Carbapenemases are enzymes produced by some bacteria which inactivate these antibiotics.
‘Over the past decade carbapenemase-producing CRE (CP-CRE) have rapidly spread around the globe and are currently considered an urgent public health threat by the Centers for Disease Control and Prevention (CDC),’ says Karim Morey of the Oregon State Public Health Lab, an author on the study. ‘Timely detection of CP-CRE is critical to patient care and infection control.’
Polymerase chain reaction (PCR), a DNA-based test, is currently the gold standard for detecting CRE, but it is expensive and requires equipment that many labs just do not have, especially in low-income countries that are large reservoirs for CRE. Carba NP is a much less expensive test that most labs should be able to afford.
In the study Morey and her colleagues evaluated the ability of the Carba NP test to properly identify 59 of the 201 clinical isolates as carbapenemase producers. Using a previously published Mayo Clinic protocol, they correctly identified 92% as being carbapenemase producers, including all strains of NDM-1 and KPC, two important types of CRE. When they adjusted the protocol to increase the inoculum size and tested again they achieved 100% sensitivity. The average time to complete a test was 2.5 hours.
‘We conclude that the Carba NP test is highly sensitive, specific and reproducible for the detection of carbapenemase production in a diverse group of organisms,’ says Morey.
This work was done as part of the Drug Resistant Organism Coordinated Regional Epidemiology Network, a statewide initiative to prevent the emergence and spread of CRE in the state of Oregon and Funded by the CDC.
EurekAlert
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Researchers at UT Southwestern Medical Center and the Gill Center for Cancer and Blood Disorders at Children’s Medical Center, Dallas, have made significant progress in defining new genetic causes of Wilms tumor, a type of kidney cancer found only in children.
Wilms tumour is the most common childhood genitourinary tract cancer and the third most common solid tumour of childhood.
“While most children with Wilms tumour are thankfully cured, those with more aggressive tumours do poorly, and we are increasingly concerned about the long-term adverse side effects of chemotherapy in Wilms tumour patients. We wanted to know – what are the genetic causes of Wilms tumour in children and what are the opportunities for targeted therapies? To answer these questions, you have to identify genes that are mutated in the cancer,” said Dr. James Amatruda, Associate Professor of Pediatrics, Molecular Biology, and Internal Medicine at UT Southwestern and senior author for the study.
Collaborating with Dr. Amatruda on the study were UT Southwestern faculty members Dr. Dinesh Rakheja, Associate Professor of Pathology and Pediatrics; Dr. Kenneth S. Chen, Assistant Instructor in Pediatrics; and Dr. Joshua T. Mendell, Professor of Molecular Biology. Dr. Jonathan Wickiser, Associate Professor in Pediatrics, and Dr. James Malter, Chair of Pathology, are also co-authors.
Previous research has identified one or two mutant genes in Wilms tumours, but only about one-third of Wilms tumors had these mutations.
“We wanted to know what genes were mutated in the other two-thirds. To accomplish this goal, we sequenced the DNA of 44 tumours and identified several new mutated genes,” said Dr. Amatruda, who holds the Nearburg Family Professorship in Pediatric Oncology Research and is an Attending Physician in the Pauline Allen Gill Center for Cancer and Blood Disorders at Children’s Medical Center. “The new genes had not been identified before. The most common, and in some ways the most biologically interesting, mutations were found in genes called DROSHA and DICER1. We found that these mutations affected the cell’s production of microRNAs, which are tiny RNA molecules that play big roles in controlling the growth of cells, and the primary effect was on a family of microRNAs called let-7.”
“Let-7 is an important microRNA that slows cell growth and in Wilms tumours in which DROSHA or DICER1 were mutated, let-7 RNA is missing, which causes the cells to grow abnormally fast,” Dr. Amatruda said.
These findings have implications for future treatment of Wilms tumour and several other childhood cancers, including neuroblastoma, germ cell tumour, and rhabdomyosarcoma.
“What’s exciting about these results is that we can begin to understand what drives the growth of different types of Wilms tumours. This is a critical first step in trying to treat the cancer based on its true molecular defect, rather than just what a tumour looks like under a microscope,” Dr. Amatruda said. “Most importantly, we begin to think in concrete terms about a therapy, which is an exciting translational goal of our work in the next few years.
UT Southwestern Medical Center
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A new blood test allowing doctors to predict which ovarian cancer patients will respond to particular types of treatment is a step closer following a new study by Manchester scientists.
Researchers from The University of Manchester and The Christie NHS Foundation Trust – both part of Manchester Cancer Research Centre – say the test could be developed and used in hospitals within the next few years.
It would mean medics could see which patients could benefit from blood vessel-targeting drugs – such as bevacizumab – in addition to conventional therapy. Meanwhilehile others who are not going to benefit would be spared the time and side effects associated with having the drug. The test would also help to reduce the cost to the NHS.
Ovarian cancer has seen little increase in survival rates over the last few decades and scientists are seeking new treatment strategies to improve the standard approach of surgery and chemotherapy.
A recent advance has been to target the development of new blood vessels within the tumour – preventing the cancer from receiving the nutrients it needs to grow.
Bevacizumab, one of the blood vessel-targeting drugs, has shown significant but modest improvements in patient survival so doctors are seeking ways to predict which patients are most likely to gain an advantage from this type of drug.
The research team looked at blood samples from patients enrolled in an international trial of bevacizumab. These patients received either standard chemotherapy treatment alone or chemotherapy plus the blood vessel-targeting drug.
Professor Gordon Jayson, Professor of Medical Oncology at The University of Manchester and Honorary Consultant at The Christie who jointly led the study, said: ‘We are keen to identify predictive biomarkers – measures that can indicate how well a patient will respond to treatment – so we can better target these drugs to patients most likely to benefit.
‘We investigated levels of a range of proteins in patients’ pre-treatment blood samples to see if any were associated with improved survival.’
The findings show that two particular proteins – Ang1 and Tie2 – could be used in combination to predict patient response. Patients with high levels of Ang1 and low levels of Tie2 were most likely to benefit from bevacizumab. Both these proteins are involved in controlling the formation of new blood vessels. Conversely, they found that patients with high levels of both proteins did not benefit from the additional drug.
Study co-author Professor Caroline Dive, from the Cancer Research UK Manchester Institute based at The University of Manchester, added: ‘We will now look to further explore the potential of using a blood test to personalise treatment for ovarian cancer patients. Moving towards a more individualised treatment plan specific for each patient and their particular tumour is key to improving outcomes for patients while sparing those unlikely to benefit from potential side effects of therapy.’
University of Manchester
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A recent breakthrough in understanding the cause of a rare, hard-to-treat allergic disorder has been made by a group of research institutions that include the University of Arkansas for Medical Sciences (UAMS) and the Arkansas Children’s Hospital Research Institute (ACHRI).
The discovery could lead to new targeted therapies for eosinophilic eophagitis (EoE). The allergic/immune condition causes inflammation of the oesophagus, usually from consuming foods such as dairy products, eggs, soy and wheat.
The condition can cause infants and toddlers to refuse food and hinder their development. Older children may have recurring abdominal pain, vomiting and trouble swallowing, while teenagers and adults typically have difficulty swallowing. Food may also become stuck in the inflamed oesophagus, creating a medical emergency.
Existing treatments for EoE are limited to prescribing long-term restrictive diets and steroid sprays to swallow.
“We hope this discovery will open the door to some additional treatment options,” said Stacie Jones, M.D., a professor in the departments of Pediatrics and Physiology & Biophysics in the UAMS College of Medicine. She is also section chief of Allergy & Immunology and leads the allergy research team ACHRI.
The study found that EoE is triggered by the interaction between epithelial cells, which help form the lining of the oesophagus, and a gene called CAPN14. It also identified a marker that can be used to measure the activity of the disease, said UAMS’ Robert Pesek, M.D., an author on the study and an assistant professor in the Department of Pediatrics in the UAMS College of Medicine.
“Currently, the only tool we have for measuring that is endoscopy, and that becomes impractical for repeated use on children,” Pesek said.
Although new treatments have yet to be realized, UAMS’ participation in EoE and other food allergy research gives Arkansas patients access to cutting-edge research and treatment expertise not available anywhere else in the state.
University of Arkansas for Medical Sciences
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People with blood type AB may be more likely to develop memory loss in later years than people with other blood types, according to a study published by Kristine Alexander, Ph.D., postdoctoral fellow in medicine, Mary Cushman, M.D., M.Sc., professor of medicine at the University of Vermont College of Medicine, and colleagues.
AB is the least common blood type, found in only about four percent of the U.S. population. The study found that people with AB blood were 82 percent more likely to develop the thinking and memory problems that can lead to dementia than people with other blood types. Previous studies have shown that people with type O blood have a lower risk of heart disease and stroke, factors that can increase the risk of memory loss and dementia.
The study was part of a larger study (the REasons for Geographic And Racial Differences in Stroke, or REGARDS Study) of more than 30,000 people followed for an average of 3.4 years. In those who had no memory or thinking problems at the beginning, the study identified 495 participants who developed thinking and memory problems, or cognitive impairment, during the study. They were compared to 587 people with no cognitive problems.
People with AB blood type made up 6 percent of the group who developed cognitive impairment, which is higher than the 4 percent found in the population.
“Our study looks at blood type and risk of cognitive impairment, but several studies have shown that factors such as high blood pressure, high cholesterol and diabetes increase the risk of cognitive impairment and dementia,” says Alexander. “Blood type is also related to other vascular conditions like stroke, so the findings highlight the connections between vascular issues and brain health. More research is needed to confirm these results.”
In the study, researchers also looked at blood levels of factor VIII, a protein that helps blood to clot. High levels of factor VIII were related to higher risk of cognitive impairment. People in this study with higher levels of factor VIII were 24 percent more likely to develop thinking and memory problems than people with lower levels of the protein. People with AB blood had a higher average level of factor VIII than people with other blood types.
“For stroke, we found that about half of the association of blood type AB with stroke was due to differences between people in levels of clotting Factor VIII, but our current study of cognitive impairment did show this finding,” says Cushman, who adds that the differences in the findings of the two studies suggests that other reasons – not yet understood – are likely playing a role in explaining the impact on of blood type AB on cognitive function. Further research is needed to determine those details.
University of Vermont
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Using advanced computer models, neuroscience researchers at the University of Copenhagen have gained new knowledge about the complex processes that cause Parkinson’s disease.
The defining symptoms of Parkinson’s disease are slow movements, muscular stiffness and shaking. There is currently no cure for the condition, so it is essential to conduct innovative research with the potential to shed some light on this terrible disruption to the central nervous system that affects one person in a thousand in Denmark. Using advanced computer models, neuroscience researchers at the University of Copenhagen have gained new knowledge about the complex processes that cause Parkinson’s disease.
Dopamine is an important neurotransmitter which affects physical and psychological functions such as motor control, learning and memory. Levels of this substance are regulated by special dopamine cells. When the level of dopamine drops, nerve cells that constitute part of the brain’s ‘stop signal’ are activated.
“This stop signal is rather like the safety lever on a motorised lawn mower: if you take your hand off the lever, the mower’s motor stops. Similarly, dopamine must always be present in the system to block the stop signal. Parkinson’s disease arises because for some reason the dopamine cells in the brain are lost, and it is known that the stop signal is being over-activated somehow or other. Many researchers have therefore considered it obvious that long-term lack of dopamine must be the cause of the distinctive symptoms that accompanies the disease. However, we can now use advanced computer simulations to challenge the existing paradigm and put forward a different theory about what actually takes place in the brain when the dopamine cells gradually die,” explains Jakob Kisbye Dreyer, Postdoc at the Department of Neuroscience and Pharmacology, University of Copenhagen.
Scanning the brain of a patient suffering from Parkinson’s disease reveals that in spite of dopamine cell death, there are no signs of a lack of dopamine – even at a comparatively late stage in the process.
“The inability to establish a lack of dopamine until advanced cases of Parkinson’s disease has been a thorn in the side of researchers for many years. On the one hand, the symptoms indicate that the stop signal is over-activated, and patients are treated accordingly with a fair degree of success. On the other hand, data prove that they are not lacking dopamine,” says Postdoc Jakob Kisbye Dreyer.
“Our calculations indicate that cell death only affects the level of dopamine very late in the process, but that symptoms can arise long before the level of the neurotransmitter starts to decline. The reason for this is that the fluctuations that normally make up a signal become weaker. In the computer model, the brain compensates for the shortage of signals by creating additional dopamine receptors. This has a positive effect initially, but as cell death progresses further, the correct signal may almost disappear. At this stage, the compensation becomes so overwhelming that even small variations in the level of dopamine trigger the stop signal – which can therefore cause the patient to develop the disease.”
University of Copenhagen
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Scientists could soon better predict a man’s risk of getting prostate cancer after a worldwide team of researchers carried out the largest-ever analysis of the cancer’s genetic biomarkers.
QUT Institute of Health and Biomedical Innovation’s Dr Jyotsna Batra and Distinguished Professor Judith Clements, who led the Australian researchers in the large consortia of research hubs around the world, said the teams analysed more than 10 million genetic markers in 80,000 men.
‘It’s the largest analysis of genetic biomarkers ever done. We found another 23 new prostate cancer risk loci (sites) on the genome in addition to the 76 identified previously,’ Dr Batra said.
‘We now have 100 genetic regions and no other cancer has had this many loci identified to be associated with it. What we are looking for is the combination effect of how these loci work together and how much they can explain the heritability of prostate cancer.
‘The indications are that these genetic variants explain 33 per cent of the familial risk of the disease.
‘These are low-risk gene variants but what we have learnt is you can’t rely on just one gene to predict risk. You have to look at the total of the 100.
‘The top one per cent of men with these variants have a 5.7-fold relative risk compared with the population average.’
Dr Batra said that, in addition to family history, incorporating information regarding carrier status of these 100 risk variants could be valuable in defining risk levels in targeted screening and prevention programs for prostate cancer.
She said the multi-ethnic analysis of 80,000 individuals with prostate cancer found some risk variants were more common in different ethnic populations.
‘The aggressive form is prevalent in Africa and we found some risk genes specific to African populations,’ she said.
‘Of the 23 new variants we found 15 were in men of European ancestry and seven in the multi-ethnic analyses.’
Dr Batra said the sufferers of the non-aggressive form of prostate cancer outnumbered those with the aggressive form in the sample of 80,000 men.
‘Only 10 per cent of prostate cancers were the aggressive form in the current analysis,’ she said.
‘So far, we haven’t identified the loci for the aggressive form of the disease – research is ongoing on this. The next sample set will have more than 100,000 people with prostate cancer,’ she said.
‘Being able to predict the aggressive form before it goes on to spread is a goal of the future research because even after the prostate is removed a few cells can go on to kill the person.’
Queensland University of Technology
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Researchers have found evidence that genetic factors may contribute to the development of language during infancy.
Scientists from the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol worked with colleagues around the world to discover a significant link between genetic changes near the ROBO2 gene and the number of words spoken by children in the early stages of language development.
Children produce words at about 10 to 15 months of age and our range of vocabulary expands as we grow – from around 50 words at 15 to 18 months, 200 words at 18 to 30 months, 14,000 words at six-years-old and then over 50,000 words by the time we leave secondary school.
The researchers found the genetic link during the ages of 15 to 18 months when toddlers typically communicate with single words only before their linguistic skills advance to two-word combinations and more complex grammatical structures.
The results shed further light on a specific genetic region on chromosome 3, which has been previously implicated in dyslexia and speech-related disorders.
The ROBO2 gene contains the instructions for making the ROBO2 protein. This protein directs chemicals in brain cells and other neuronal cell formations that may help infants to develop language but also to produce sounds.
The ROBO2 protein also closely interacts with other ROBO proteins that have previously been linked to problems with reading and the storage of speech sounds.
Dr Beate St Pourcain, who jointly led the research with Professor Davey Smith at the MRC Integrative Epidemiology Unit, said: ‘This research helps us to better understand the genetic factors which may be involved in the early language development in healthy children, particularly at a time when children speak with single words only, and strengthens the link between ROBO proteins and a variety of linguistic skills in humans.”
Dr Claire Haworth, one of the lead authors, based at the University of Warwick, commented: “In this study we found that results using DNA confirm those we get from twin studies about the importance of genetic influences for language development. This is good news as it means that current DNA-based investigations can be used to detect most of the genetic factors that contribute to these early language skills.’
University of Bristol
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New targets for treating pulmonary hypertension found
, /in E-News /by 3wmediaTwo new potential therapeutic targets for the treatment of pulmonary arterial hypertension, a deadly disease marked by high blood pressure in the lungs, have been identified by researchers at the University of Illinois at Chicago.
Early symptoms of pulmonary arterial hypertension include shortness of breath and exercise intolerance. As the disease progresses, patients may require oxygen supplementation and lung transplantation. Heart failure can develop and is a major cause of death in the disease.
Most cases of pulmonary hypertension are of unknown cause, though the condition often occurs in association with other diseases, including scleroderma, congenital heart disease and liver disease. One of the underlying factors driving the increased blood pressure in the lungs is a narrowing of the pulmonary blood vessels. This narrowing can be due to an abnormal proliferation of cells within the walls of the blood vessels, particularly in the smooth muscle cells of the pulmonary artery.
Jiwang Chen, research assistant professor of critical care medicine, sleep and allergy in the UIC College of Medicine, and his colleagues investigated the molecular mechanisms behind the abnormal proliferation of smooth muscle cells in the pulmonary artery and discovered two ways that the proliferation could be suppressed.
They knew that an enzyme, sphingosine kinase 1, that produces a signalling molecule called sphingosine-1-phosphate (S1P), had been linked to the abnormal growth of cells in cancer, including lung cancer.
“The characteristic proliferation of cells that line the blood vessels in pulmonary hypertension is similar to the abnormal growth and reproduction of cells that form cancerous tumours,” says Chen. “We wanted to see if sphingosine kinase 1 and S1P were involved in the development of pulmonary arterial hypertension.”
Looking at samples of lung tissue from patients, Chen and colleagues found that patients with pulmonary arterial hypertension had significantly elevated levels of both the enzyme and the signalling molecule it produces. They found similarly elevated levels of both molecules in mouse and rat models of pulmonary hypertension.
Knockout mice lacking the gene for sphingosine kinase 1 were less likely than normal mice to develop pulmonary hypertension when exposed to the low-oxygen conditions used to induce the disease in the laboratory.
Drugs that either suppress production of sphingosine kinase 1 or block the signalling of S1P through its receptors on smooth muscle cells prevented mice from developing pulmonary hypertension in low-oxygen conditions.
The researchers also showed in mice that over-production of sphingosine kinase 1 and S1P promote the proliferation of pulmonary artery smooth muscle cells.
“Our results yield two new potential targets for the development of drugs to treat or prevent the progression of pulmonary arterial hypertension,” Chen said.
“By blocking the binding site for S1P or suppressing the production of S1P, like we did in our experimental rodent model, we can reduce the proliferation of pulmonary artery smooth muscle cells, which is a major contributor to pulmonary hypertension.” University of Illinois at Chicago
UV light can turn gene into source of skin cancers, researchers find
, /in E-News /by 3wmediaA genetic mutation caused by ultraviolet light is likely the driving force behind millions of human skin cancers, according to researchers at the Stanford University School of Medicine.
The mutation occurs in a gene called KNSTRN, which is involved in helping cells divide their DNA equally during cell division.
Genes that cause cancer when mutated are known as oncogenes. Although KNSTRN hasn’t been previously implicated as a cause of human cancers, the research suggests it may be one of the most commonly mutated oncogenes in the world.
“This previously unknown oncogene is activated by sunlight and drives the development of cutaneous squamous cell carcinomas,” said Paul Khavari, MD, PhD, the Carl J. Herzog Professor in Dermatology in the School of Medicine and chair of the Department of Dermatology. “Our research shows that skin cancers arise differently from other cancers, and that a single mutation can cause genomic catastrophe.”
Cutaneous squamous cell carcinoma is the second most common cancer in humans. More than 1 million new cases are diagnosed globally each year. The researchers found that a particular region of KNSTRN is mutated in about 20 percent of cutaneous squamous cell carcinomas and in about 5 percent of melanomas.
Lee and Khavari made the discovery while investigating the genetic causes of cutaneous squamous cell carcinoma. They compared the DNA sequences of genes from the tumour cells with those of normal skin and looked for mutations that occurred only in the tumours. They found 336 candidate genes for further study, including some familiar culprits. The top two most commonly mutated genes were CDKN2A and TP53, which were already known to be associated with squamous cell carcinoma.
The third most commonly mutated gene, KNSTRN, was a surprise. It encodes a protein that helps to form the kinetochore — a structure that serves as a kind of handle used to pull pairs of newly replicated chromosomes to either end of the cell during cell division. Sequestering the DNA at either end of the cell allows the cell to split along the middle to form two daughter cells, each with the proper complement of chromosomes.
If the chromosomes don’t separate correctly, the daughter cells will have abnormal amounts of DNA. These cells with extra or missing chromosomes are known as aneuploid, and they are often severely dysfunctional. They tend to misread cellular cues and to behave erratically. Aneuploidy is a critical early step toward the development of many types of cancer.
The mutation in the KNSTRN gene was caused by the replacement of a single nucleotide, called a cytosine, with another, called a thymine, within a specific, short stretch of DNA. The swap is indicative of a cell’s attempt to repair damage from high-energy ultraviolet rays, such as those found in sunlight.
“Mutations at this UV hotspot are not found in any of the other cancers we investigated,” said Khavari. “They occur only in skin cancers.”
The researchers found the UV-induced KNSTRN mutation in about 20 percent of actinic keratoses — a premalignant skin condition that often progresses to squamous cell carcinoma — but never in 122 samples of normal skin, indicating the mutation is likely to be an early event in the development of squamous cell carcinomas.
Furthermore, overexpression of mutant KNSTRN in laboratory-grown human skin cells disrupted their ability to segregate their DNA during cell division and enhanced the growth of cancer cells in a mouse model of squamous cell carcinoma.
Finally, Lee compared five patient-derived squamous cell carcinomas that had the KNSTRN mutation with five samples that did not have the mutation. Although both sets of cells were aneuploid, those with the mutation had the most severely abnormal genomes. Stanford University School of Medicine
Inexpensive lab test identifies resistant infections in hours
, /in E-News /by 3wmediaResearchers from Oregon State Public Health Lab have modified the protocol for a relatively new test for a dangerous form of antibiotic resistance, increasing its specificity to 100 percent. Their research, confirming the reliability of a test that can provide results in hours and is simple and inexpensive enough to be conducted in practically any clinical laboratory.
The test, called Carba NP, originally developed by Patrice Nordmann and Laurent Poirel at the University of Fribourg, Switzerland, and Laurent Dortet of the University Hospital of the South-Paris Medical School, France, allows for rapid identification of carbapenem-resistant Enterobacteriaceae (CRE), often referred to in the media as ‘super bugs’ for their ability to resist most major antibiotics. Carbapenems are an important class of powerful antibiotics for treating severe infections caused by multidrug-resistant Gram negative bacteria. Carbapenemases are enzymes produced by some bacteria which inactivate these antibiotics.
‘Over the past decade carbapenemase-producing CRE (CP-CRE) have rapidly spread around the globe and are currently considered an urgent public health threat by the Centers for Disease Control and Prevention (CDC),’ says Karim Morey of the Oregon State Public Health Lab, an author on the study. ‘Timely detection of CP-CRE is critical to patient care and infection control.’
Polymerase chain reaction (PCR), a DNA-based test, is currently the gold standard for detecting CRE, but it is expensive and requires equipment that many labs just do not have, especially in low-income countries that are large reservoirs for CRE. Carba NP is a much less expensive test that most labs should be able to afford.
In the study Morey and her colleagues evaluated the ability of the Carba NP test to properly identify 59 of the 201 clinical isolates as carbapenemase producers. Using a previously published Mayo Clinic protocol, they correctly identified 92% as being carbapenemase producers, including all strains of NDM-1 and KPC, two important types of CRE. When they adjusted the protocol to increase the inoculum size and tested again they achieved 100% sensitivity. The average time to complete a test was 2.5 hours.
‘We conclude that the Carba NP test is highly sensitive, specific and reproducible for the detection of carbapenemase production in a diverse group of organisms,’ says Morey.
This work was done as part of the Drug Resistant Organism Coordinated Regional Epidemiology Network, a statewide initiative to prevent the emergence and spread of CRE in the state of Oregon and Funded by the CDC. EurekAlert
Researchers find new gene mutations for Wilms Tumour
, /in E-News /by 3wmediaResearchers at UT Southwestern Medical Center and the Gill Center for Cancer and Blood Disorders at Children’s Medical Center, Dallas, have made significant progress in defining new genetic causes of Wilms tumor, a type of kidney cancer found only in children.
Wilms tumour is the most common childhood genitourinary tract cancer and the third most common solid tumour of childhood.
“While most children with Wilms tumour are thankfully cured, those with more aggressive tumours do poorly, and we are increasingly concerned about the long-term adverse side effects of chemotherapy in Wilms tumour patients. We wanted to know – what are the genetic causes of Wilms tumour in children and what are the opportunities for targeted therapies? To answer these questions, you have to identify genes that are mutated in the cancer,” said Dr. James Amatruda, Associate Professor of Pediatrics, Molecular Biology, and Internal Medicine at UT Southwestern and senior author for the study.
Collaborating with Dr. Amatruda on the study were UT Southwestern faculty members Dr. Dinesh Rakheja, Associate Professor of Pathology and Pediatrics; Dr. Kenneth S. Chen, Assistant Instructor in Pediatrics; and Dr. Joshua T. Mendell, Professor of Molecular Biology. Dr. Jonathan Wickiser, Associate Professor in Pediatrics, and Dr. James Malter, Chair of Pathology, are also co-authors.
Previous research has identified one or two mutant genes in Wilms tumours, but only about one-third of Wilms tumors had these mutations.
“We wanted to know what genes were mutated in the other two-thirds. To accomplish this goal, we sequenced the DNA of 44 tumours and identified several new mutated genes,” said Dr. Amatruda, who holds the Nearburg Family Professorship in Pediatric Oncology Research and is an Attending Physician in the Pauline Allen Gill Center for Cancer and Blood Disorders at Children’s Medical Center. “The new genes had not been identified before. The most common, and in some ways the most biologically interesting, mutations were found in genes called DROSHA and DICER1. We found that these mutations affected the cell’s production of microRNAs, which are tiny RNA molecules that play big roles in controlling the growth of cells, and the primary effect was on a family of microRNAs called let-7.”
“Let-7 is an important microRNA that slows cell growth and in Wilms tumours in which DROSHA or DICER1 were mutated, let-7 RNA is missing, which causes the cells to grow abnormally fast,” Dr. Amatruda said.
These findings have implications for future treatment of Wilms tumour and several other childhood cancers, including neuroblastoma, germ cell tumour, and rhabdomyosarcoma.
“What’s exciting about these results is that we can begin to understand what drives the growth of different types of Wilms tumours. This is a critical first step in trying to treat the cancer based on its true molecular defect, rather than just what a tumour looks like under a microscope,” Dr. Amatruda said. “Most importantly, we begin to think in concrete terms about a therapy, which is an exciting translational goal of our work in the next few years. UT Southwestern Medical Center
New blood test could offer more tailored treatment of ovarian cancer
, /in E-News /by 3wmediaA new blood test allowing doctors to predict which ovarian cancer patients will respond to particular types of treatment is a step closer following a new study by Manchester scientists.
Researchers from The University of Manchester and The Christie NHS Foundation Trust – both part of Manchester Cancer Research Centre – say the test could be developed and used in hospitals within the next few years.
It would mean medics could see which patients could benefit from blood vessel-targeting drugs – such as bevacizumab – in addition to conventional therapy. Meanwhilehile others who are not going to benefit would be spared the time and side effects associated with having the drug. The test would also help to reduce the cost to the NHS.
Ovarian cancer has seen little increase in survival rates over the last few decades and scientists are seeking new treatment strategies to improve the standard approach of surgery and chemotherapy.
A recent advance has been to target the development of new blood vessels within the tumour – preventing the cancer from receiving the nutrients it needs to grow.
Bevacizumab, one of the blood vessel-targeting drugs, has shown significant but modest improvements in patient survival so doctors are seeking ways to predict which patients are most likely to gain an advantage from this type of drug.
The research team looked at blood samples from patients enrolled in an international trial of bevacizumab. These patients received either standard chemotherapy treatment alone or chemotherapy plus the blood vessel-targeting drug.
Professor Gordon Jayson, Professor of Medical Oncology at The University of Manchester and Honorary Consultant at The Christie who jointly led the study, said: ‘We are keen to identify predictive biomarkers – measures that can indicate how well a patient will respond to treatment – so we can better target these drugs to patients most likely to benefit.
‘We investigated levels of a range of proteins in patients’ pre-treatment blood samples to see if any were associated with improved survival.’
The findings show that two particular proteins – Ang1 and Tie2 – could be used in combination to predict patient response. Patients with high levels of Ang1 and low levels of Tie2 were most likely to benefit from bevacizumab. Both these proteins are involved in controlling the formation of new blood vessels. Conversely, they found that patients with high levels of both proteins did not benefit from the additional drug.
Study co-author Professor Caroline Dive, from the Cancer Research UK Manchester Institute based at The University of Manchester, added: ‘We will now look to further explore the potential of using a blood test to personalise treatment for ovarian cancer patients. Moving towards a more individualised treatment plan specific for each patient and their particular tumour is key to improving outcomes for patients while sparing those unlikely to benefit from potential side effects of therapy.’ University of Manchester
Researchers help discover genetic key to food allergy condition
, /in E-News /by 3wmediaA recent breakthrough in understanding the cause of a rare, hard-to-treat allergic disorder has been made by a group of research institutions that include the University of Arkansas for Medical Sciences (UAMS) and the Arkansas Children’s Hospital Research Institute (ACHRI).
The discovery could lead to new targeted therapies for eosinophilic eophagitis (EoE). The allergic/immune condition causes inflammation of the oesophagus, usually from consuming foods such as dairy products, eggs, soy and wheat.
The condition can cause infants and toddlers to refuse food and hinder their development. Older children may have recurring abdominal pain, vomiting and trouble swallowing, while teenagers and adults typically have difficulty swallowing. Food may also become stuck in the inflamed oesophagus, creating a medical emergency.
Existing treatments for EoE are limited to prescribing long-term restrictive diets and steroid sprays to swallow.
“We hope this discovery will open the door to some additional treatment options,” said Stacie Jones, M.D., a professor in the departments of Pediatrics and Physiology & Biophysics in the UAMS College of Medicine. She is also section chief of Allergy & Immunology and leads the allergy research team ACHRI.
The study found that EoE is triggered by the interaction between epithelial cells, which help form the lining of the oesophagus, and a gene called CAPN14. It also identified a marker that can be used to measure the activity of the disease, said UAMS’ Robert Pesek, M.D., an author on the study and an assistant professor in the Department of Pediatrics in the UAMS College of Medicine.
“Currently, the only tool we have for measuring that is endoscopy, and that becomes impractical for repeated use on children,” Pesek said.
Although new treatments have yet to be realized, UAMS’ participation in EoE and other food allergy research gives Arkansas patients access to cutting-edge research and treatment expertise not available anywhere else in the state. University of Arkansas for Medical Sciences
Study finds blood type and memory loss link
, /in E-News /by 3wmediaPeople with blood type AB may be more likely to develop memory loss in later years than people with other blood types, according to a study published by Kristine Alexander, Ph.D., postdoctoral fellow in medicine, Mary Cushman, M.D., M.Sc., professor of medicine at the University of Vermont College of Medicine, and colleagues.
AB is the least common blood type, found in only about four percent of the U.S. population. The study found that people with AB blood were 82 percent more likely to develop the thinking and memory problems that can lead to dementia than people with other blood types. Previous studies have shown that people with type O blood have a lower risk of heart disease and stroke, factors that can increase the risk of memory loss and dementia.
The study was part of a larger study (the REasons for Geographic And Racial Differences in Stroke, or REGARDS Study) of more than 30,000 people followed for an average of 3.4 years. In those who had no memory or thinking problems at the beginning, the study identified 495 participants who developed thinking and memory problems, or cognitive impairment, during the study. They were compared to 587 people with no cognitive problems.
People with AB blood type made up 6 percent of the group who developed cognitive impairment, which is higher than the 4 percent found in the population.
“Our study looks at blood type and risk of cognitive impairment, but several studies have shown that factors such as high blood pressure, high cholesterol and diabetes increase the risk of cognitive impairment and dementia,” says Alexander. “Blood type is also related to other vascular conditions like stroke, so the findings highlight the connections between vascular issues and brain health. More research is needed to confirm these results.”
In the study, researchers also looked at blood levels of factor VIII, a protein that helps blood to clot. High levels of factor VIII were related to higher risk of cognitive impairment. People in this study with higher levels of factor VIII were 24 percent more likely to develop thinking and memory problems than people with lower levels of the protein. People with AB blood had a higher average level of factor VIII than people with other blood types.
“For stroke, we found that about half of the association of blood type AB with stroke was due to differences between people in levels of clotting Factor VIII, but our current study of cognitive impairment did show this finding,” says Cushman, who adds that the differences in the findings of the two studies suggests that other reasons – not yet understood – are likely playing a role in explaining the impact on of blood type AB on cognitive function. Further research is needed to determine those details. University of Vermont
Researchers debunk myth about Parkinson’s disease
, /in E-News /by 3wmediaUsing advanced computer models, neuroscience researchers at the University of Copenhagen have gained new knowledge about the complex processes that cause Parkinson’s disease.
The defining symptoms of Parkinson’s disease are slow movements, muscular stiffness and shaking. There is currently no cure for the condition, so it is essential to conduct innovative research with the potential to shed some light on this terrible disruption to the central nervous system that affects one person in a thousand in Denmark. Using advanced computer models, neuroscience researchers at the University of Copenhagen have gained new knowledge about the complex processes that cause Parkinson’s disease.
Dopamine is an important neurotransmitter which affects physical and psychological functions such as motor control, learning and memory. Levels of this substance are regulated by special dopamine cells. When the level of dopamine drops, nerve cells that constitute part of the brain’s ‘stop signal’ are activated.
“This stop signal is rather like the safety lever on a motorised lawn mower: if you take your hand off the lever, the mower’s motor stops. Similarly, dopamine must always be present in the system to block the stop signal. Parkinson’s disease arises because for some reason the dopamine cells in the brain are lost, and it is known that the stop signal is being over-activated somehow or other. Many researchers have therefore considered it obvious that long-term lack of dopamine must be the cause of the distinctive symptoms that accompanies the disease. However, we can now use advanced computer simulations to challenge the existing paradigm and put forward a different theory about what actually takes place in the brain when the dopamine cells gradually die,” explains Jakob Kisbye Dreyer, Postdoc at the Department of Neuroscience and Pharmacology, University of Copenhagen.
Scanning the brain of a patient suffering from Parkinson’s disease reveals that in spite of dopamine cell death, there are no signs of a lack of dopamine – even at a comparatively late stage in the process.
“The inability to establish a lack of dopamine until advanced cases of Parkinson’s disease has been a thorn in the side of researchers for many years. On the one hand, the symptoms indicate that the stop signal is over-activated, and patients are treated accordingly with a fair degree of success. On the other hand, data prove that they are not lacking dopamine,” says Postdoc Jakob Kisbye Dreyer.
“Our calculations indicate that cell death only affects the level of dopamine very late in the process, but that symptoms can arise long before the level of the neurotransmitter starts to decline. The reason for this is that the fluctuations that normally make up a signal become weaker. In the computer model, the brain compensates for the shortage of signals by creating additional dopamine receptors. This has a positive effect initially, but as cell death progresses further, the correct signal may almost disappear. At this stage, the compensation becomes so overwhelming that even small variations in the level of dopamine trigger the stop signal – which can therefore cause the patient to develop the disease.” University of Copenhagen
New gene research helps pinpoint prostate cancer risk
, /in E-News /by 3wmediaScientists could soon better predict a man’s risk of getting prostate cancer after a worldwide team of researchers carried out the largest-ever analysis of the cancer’s genetic biomarkers.
QUT Institute of Health and Biomedical Innovation’s Dr Jyotsna Batra and Distinguished Professor Judith Clements, who led the Australian researchers in the large consortia of research hubs around the world, said the teams analysed more than 10 million genetic markers in 80,000 men.
‘It’s the largest analysis of genetic biomarkers ever done. We found another 23 new prostate cancer risk loci (sites) on the genome in addition to the 76 identified previously,’ Dr Batra said.
‘We now have 100 genetic regions and no other cancer has had this many loci identified to be associated with it. What we are looking for is the combination effect of how these loci work together and how much they can explain the heritability of prostate cancer.
‘The indications are that these genetic variants explain 33 per cent of the familial risk of the disease.
‘These are low-risk gene variants but what we have learnt is you can’t rely on just one gene to predict risk. You have to look at the total of the 100.
‘The top one per cent of men with these variants have a 5.7-fold relative risk compared with the population average.’
Dr Batra said that, in addition to family history, incorporating information regarding carrier status of these 100 risk variants could be valuable in defining risk levels in targeted screening and prevention programs for prostate cancer.
She said the multi-ethnic analysis of 80,000 individuals with prostate cancer found some risk variants were more common in different ethnic populations.
‘The aggressive form is prevalent in Africa and we found some risk genes specific to African populations,’ she said.
‘Of the 23 new variants we found 15 were in men of European ancestry and seven in the multi-ethnic analyses.’
Dr Batra said the sufferers of the non-aggressive form of prostate cancer outnumbered those with the aggressive form in the sample of 80,000 men.
‘Only 10 per cent of prostate cancers were the aggressive form in the current analysis,’ she said.
‘So far, we haven’t identified the loci for the aggressive form of the disease – research is ongoing on this. The next sample set will have more than 100,000 people with prostate cancer,’ she said.
‘Being able to predict the aggressive form before it goes on to spread is a goal of the future research because even after the prostate is removed a few cells can go on to kill the person.’ Queensland University of Technology
How learning to talk is in the genes
, /in E-News /by 3wmediaResearchers have found evidence that genetic factors may contribute to the development of language during infancy.
Scientists from the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol worked with colleagues around the world to discover a significant link between genetic changes near the ROBO2 gene and the number of words spoken by children in the early stages of language development.
Children produce words at about 10 to 15 months of age and our range of vocabulary expands as we grow – from around 50 words at 15 to 18 months, 200 words at 18 to 30 months, 14,000 words at six-years-old and then over 50,000 words by the time we leave secondary school.
The researchers found the genetic link during the ages of 15 to 18 months when toddlers typically communicate with single words only before their linguistic skills advance to two-word combinations and more complex grammatical structures.
The results shed further light on a specific genetic region on chromosome 3, which has been previously implicated in dyslexia and speech-related disorders.
The ROBO2 gene contains the instructions for making the ROBO2 protein. This protein directs chemicals in brain cells and other neuronal cell formations that may help infants to develop language but also to produce sounds.
The ROBO2 protein also closely interacts with other ROBO proteins that have previously been linked to problems with reading and the storage of speech sounds.
Dr Beate St Pourcain, who jointly led the research with Professor Davey Smith at the MRC Integrative Epidemiology Unit, said: ‘This research helps us to better understand the genetic factors which may be involved in the early language development in healthy children, particularly at a time when children speak with single words only, and strengthens the link between ROBO proteins and a variety of linguistic skills in humans.”
Dr Claire Haworth, one of the lead authors, based at the University of Warwick, commented: “In this study we found that results using DNA confirm those we get from twin studies about the importance of genetic influences for language development. This is good news as it means that current DNA-based investigations can be used to detect most of the genetic factors that contribute to these early language skills.’ University of Bristol