One of 100,000 children is born with Menkes disease, a genetic disorder that affects the body’s ability to properly absorb copper from food and leads to neurodegeneration, seizures, impaired movement, stunted growth and, often, death before age 3. Now, a team of biochemistry researchers at the University of Missouri has published conclusive scientific evidence that the gene ATP7A is essential for the dietary absorption of the nutrient copper. Their work with laboratory mice also provides a greater understanding of how this gene impacts Menkes disease as scientists search for a treatment.

Humans cannot survive if their bodies are lacking the ATP7A gene, yet children can develop Menkes disease when the gene is mutated or missing. Previously, scientists did not have a good model to test the gene’s function or develop an understanding of the underlying causes of the disease symptoms. In his new study, Michael Petris, associate professor of biochemistry, was able to modify mice so that they were missing the ATP7A gene in certain areas of the body, specifically the intestinal track where nutrient absorption takes place.

‘These findings help us to understand where in the body the function of this gene is vital and how the loss of the gene in certain tissues can give rise to Menke’s disease,’ said Petris, who is a researcher in the Bond Life Sciences Center and holds an appointment in the Department of Nutrition and Exercise Physiology. ‘We want to continue to explore the underlying biology of Menke’s disease to determine where we should focus our research efforts in the future. If we know which organs or tissues are most responsible for transporting copper throughout the body, we can focus on making sure the gene is expressed in those areas. This disease is ideal for gene therapy down the road.’

Petris found that young mice missing the ATP7A gene in their intestinal cells were unable to absorb copper from food, resulting in an overall copper deficiency that mimics symptoms of Menkes disease in children. Petris says it’s vital to ensure that the developing newborns absorb enough copper during the neonatal period when the demand for the mineral is highest.

‘Copper is a little-appreciated but essential trace mineral in all body tissues,’ Petris said. ‘Cells cannot properly use oxygen without copper; it helps in the formation of red blood cells, and it helps keep the blood vessels, nerves, skin, immune system and bones healthy. Normally, people absorb enough copper through their food. However, in the bodies of those with Menkes disease, copper begins to accumulate at abnormally low levels in the liver and brain and at higher than normal levels in the kidney and intestinal lining.’

Newborn screening for this disorder is not routine, and early detection is infrequent because it can arise spontaneously in families, Petris said. Many times, the disease is not detected until the symptoms are noticed, and by that time, it can be too late for any aggressive treatments.

‘The clinical signs of Menkes disease are subtle in the beginning, so the disease is rarely treated early enough to make a significant difference,’ he said. ‘However, a single dose of copper injected into mice within a few days of birth restored normal growth and life expectancy. Early intervention was critical because treatment that began after symptoms developed wasn’t successful.’

Petris says that understanding the roles of copper in biology may have far-reaching health implications for the general population because copper underpins many facets of biology, including the growth of cancer tumours and the formation of toxic proteins in Alzheimer’s disease.

The development of these mice provides a novel experimental system in which to test treatments for patients with this disease. The early-stage results of this research are promising, but additional studies are needed. University of Missouri

The risk of kidney failure is greater for people with chronic kidney disease who also have atrial fibrillation, one of the most common forms of irregular heart rhythm in adults, according to a new study by researchers at UCSF and the Kaiser Permanente Northern California Division of Research.
The finding opens the way for further studies into the relationship between the two factors, which could lead to new treatment approaches that would improve outcomes for people with chronic kidney disease.
Many people who suffer from chronic kidney disease progressively lose their kidney function over time and eventually develop a condition called end-stage renal disease – the complete failure of the kidneys – placing them in need of lifelong dialysis or a kidney transplant.
Doctors have known that patients with chronic kidney disease or end-stage renal disease commonly have atrial fibrillation and as a result are more likely to have a stroke or to die. However, the long-term impact of atrial fibrillation on kidney function among patients with known chronic kidney disease has been unknown.
The new study involved 206,229 adults with chronic kidney disease who were drawn from members of Kaiser Permanente Northern California, a large integrated health care delivery system.. Over the course of about five years, approximately 16,400 patients developed atrial fibrillation, and those who did were 67 percent more likely to progress to end-stage renal disease compared with patients who had chronic kidney disease but did not develop atrial fibrillation.
‘These novel findings expand on previous knowledge by highlighting that atrial fibrillation is linked to a worse kidney prognosis in patients with underlying kidney dysfunction,’ said kidney specialist Nisha Bansal, MD, an assistant professor in the Division of Nephrology at UCSF.
‘There is a knowledge gap about the long-term impact of atrial fibrillation on the risk of adverse kidney-related outcomes in patients with chronic kidney disease,’ said senior author Alan S. Go, MD, director of the Comprehensive Clinical Research Unit at the Kaiser Permanente Division of Research. ‘This study addresses that gap and may have important implications for clinical management by providing better prognostic information and leading to future work determining how to improve outcomes in this high-risk group of patients.’
UCSF is one of the world’s leading centres for kidney disease treatment, research and education. Its Division of Nephrology is ranked among the best programs in the nation by U.S. News & World Report.
People who have chronic kidney disease fall into a spectrum in terms of how severe their disease is.
At one end are those who have very minor loss of kidney function. They may not have any symptoms at all, and only by applying a simple blood test can doctors properly diagnose their disease.
At the other end of the spectrum are the people who have progressed to end-stage renal disease, which is basically complete kidney failure. They require lifelong dialysis or a kidney transplant. Some people progress rapidly to end-stage renal disease while others may live for decades without ever progressing.
Doctors are interested in understanding the factors that place patients at greater risk for end-stage renal disease, Bansal said, because it may be possible to address those factors through medications or lifestyle changes like diet or exercise.
Bansal added, however, that while the two conditions are intertwined, scientists do not know exactly which specific genes, pathways and biological mechanisms connect irregular heartbeat to declines in kidney function. Neither do they yet know the extent to which treating atrial fibrillation will improve outcomes for people with chronic kidney disease. University of California – San Francisco

Montréal scientists identified the DOCK1 protein as a potential target to reduce the progression of metastases in patients suffering from breast cancer, the most common type of cancer in women.

Dr. Côté’s laboratory is interested in metastasis, which is the spread of cancer from an organ (or part of an organ) to another. Nearly 90 per cent of cancer patient deaths are attributable to metastasis, thus explaining the importance of understanding the underlying cellular and molecular mechanisms of this harmful process.

‘Despite important breakthroughs in breast cancer treatment, few mechanisms are known to explain the spread of metastases,’ says Dr. Côté, Director of the Cytoskeletal Organization and Cell Migration research unit at the IRCM. ‘We are looking to identify the proteins that regulate the metastatic process so that new agents can be developed and combined with current treatments.’

Two major breast cancer subtypes, HER2+ and Basal, have a tendency to be metastatic and recurrent, and are ultimately associated to a poor survival rate. Research at the IRCM was conducted on the HER2+ type (Human Epidermal growth factor Receptor 2), which represents approximately 25 per cent of breast cancer cases. HER2 positive tumours tend to develop and spread more quickly than other types of tumours.

‘By studying a genetic mouse model with HER2+ breast cancer, we identified the protein DOCK1 as an important regulator of metastasis,’ explains Mélanie Laurin, doctoral student in Dr. Côté’s laboratory and first author of the study. ‘When we eliminated this protein in mice, our results showed a significant decrease in lung metastases. We also discovered that the DOCK1 protein contributes to the growth of tumours.’

‘To show the correlation between the expression of DOCK1 and breast cancer prognosis, we performed an analysis of several databases of patient genic,’ adds Dr. Benjamin Haibe-Kains, researcher at the IRCM who collaborated with Dr. Côté’s team. ‘We did indeed discover that high levels of DOCK1 in HER2+ or Basal breast cancer patients are associated with a lower prognosis, or recurrence of the disease.’

‘Our work defined a new molecule required for the progression of breast cancer to the metastatic stage and allowed us to identify new markers that could become potential targets to stop the progression of metastases,’ concludes Dr. Côté. ‘We also showed that a chemical inhibitor of the DOCK1 protein, developed by Dr. Yoshinori Fukui, our collaborator in Japan, can stop the migration of cancerous cells. These results could eventually lead to the development of drugs that would limit the progression of metastatic breast cancer and could thereby improve patient prognosis.’ Institut de recherches cliniques de Montréal

Scientists at Washington University School of Medicine in St. Louis have helped identify many of the biomarkers for Alzheimer’s disease that could potentially predict which patients will develop the disorder later in life. Now, studying spinal fluid samples and health data from 201 research participants at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center, the researchers have shown the markers are accurate predictors of Alzheimer’s years before symptoms develop.
‘We wanted to see if one marker was better than the other in predicting which of our participants would get cognitive impairment and when they would get it,’ said Catherine Roe, PhD, research assistant professor of neurology. ‘We found no differences in the accuracy of the biomarkers.’
The researchers evaluated markers such as the buildup of amyloid plaques in the brain, newly visible thanks to an imaging agent developed in the last decade; levels of various proteins in the cerebrospinal fluid, such as the amyloid fragments that are the principal ingredient of brain plaques; and the ratios of one protein to another in the cerebrospinal fluid, such as different forms of the brain cell structural protein tau.
The markers were studied in volunteers whose ages ranged from 45 to 88. On average, the data available on study participants spanned four years, with the longest recorded over 7.5 years.
The researchers found that all of the markers were equally good at identifying subjects who were likely to develop cognitive problems and at predicting how soon they would become noticeably impaired.
Next, the scientists paired the biomarkers data with demographic information, testing to see if sex, age, race, education and other factors could improve their predictions.
‘Sex, age and race all helped to predict who would develop cognitive impairment,’ Roe said. ‘Older participants, men and African Americans were more likely to become cognitively impaired than those who were younger, female and Caucasian.’
Roe described the findings as providing more evidence that scientists can detect Alzheimer’s disease years before memory loss and cognitive decline become apparent.
‘We can better predict future cognitive impairment when we combine biomarkers with patient characteristics,’ she said. ‘Knowing how accurate biomarkers are is important if we are going to some day be able to treat Alzheimer’s before symptoms and slow or prevent the disease.’
Clinical trials are already underway at Washington University and elsewhere to determine if treatments prior to symptoms can prevent or delay inherited forms of Alzheimer’s disease. Reliable biomarkers for Alzheimer’s should one day make it possible to test the most successful treatments in the much more common sporadic forms of Alzheimer’s. Washington University School of Medicine