An international team of researchers has identified genomic mutations for Carey-Fineman-Ziter (CFZS) syndrome, a very rare congenital myopathy (inherited muscle disorder) characterized by facial weakness, a small or retracted chin, a cleft palate and curvature of the spine (scoliosis), among other symptoms. The researchers determined that CFZS is caused by mutations in the gene MYMK that encodes for the protein myomaker. This protein is necessary for the fusion of muscle cells (myoblasts) into muscle fibres (myotubes) during the development of an embryo and the regeneration of muscle cells after injury.
"Advances in genomics technology and the power of team science have enabled us to identify the cause of this very rare disease 35 years after it was first described by Dr. John Carey and colleagues from the University of Utah," said National Institutes of Health Director Francis S. Collins, M.D., Ph.D., a co-author of the study.
"This discovery will improve physicians’ ability to diagnose this disease and offer families accurate genetic counselling and treatment," said Irini Manoli, M.D., Ph.D., co-lead author and a physician scientist and staff clinician in the Medical Genomics and Metabolic Genetics Branch at the National Human Genome Research Institute (NHGRI), part of NIH. People affected with CFZS have sometimes been misdiagnosed with Moebius syndrome, another very rare disorder characterized by facial paralysis.
Dr. Manoli said that uncovering that cell-cell fusion deficits can lead to congenital myopathies (inherited muscle disease) opens a new path of exploration for therapies for CFZS and other muscular diseases and tools for regenerating muscle. "In addition," she said, "this rare genetic syndrome provides novel insights into the effects of muscle development on craniofacial and skeletal bone formation."
The goal of the study was to learn more about the genetics and clinical characteristics of Moebius syndrome and other congenital facial weakness disorders. Toward this end, the consortium brought 63 people to the NIH Clinical Center affected with Moebius syndrome and other inherited facial weakness disorders, and their families for detailed multi-system evaluations, including brain and muscle imaging studies and muscle biopsies. The researchers collaborated through the Opportunities for Collaborative Research at the NIH Clinical Center, a new funding mechanism that encourages intramural and extramural researchers to work together at the NIH Clinical Center.
Researchers performed detailed phenotyping (identifying physical traits that are the result of a DNA sequence). They also employed the most up-to-date genomic tools, including exome sequencing of blood DNA in affected siblings from three unrelated families, as well as a muscle biopsy in one of the affected individuals. To identify the genomic mutations associated with CFZS, three laboratories – led separately by Elizabeth Engle, M.D., at the Boston Children’s Hospital, Stephen Robertson, M.D., from the University of Otago and John Carey, M.D., at the University of Utah – analysed exome sequence data from each of the three families. Among the genes harbouring mutations identified in each family, only the gene MYMK was common to all three. A knockout mouse model (genomically altered mice that are bred to lack a specific gene) displayed a complete lack of muscle development, leading to early death of the newborn mice, making this gene a promising candidate for further studies.
Using CRISPR-Cas9 technology, a tool for editing DNA at precise locations, a team led by Silvio Alessandro Di Gioia, Ph.D., and Dr. Engle, generated zebrafish with a mutated mymk gene. Affected mutant zebrafish were smaller and had abnormal muscle development and jaw deformities, resembling the patient phenotype. The researchers then performed further functional studies to validate the severity of each of the genomic mutations.
The researchers were able to correct affected zebrafish’s muscles by injecting the normal human MYMK gene product into the mutant fish. This success lends hope for restoring MYMK function in muscles as a treatment for CFZS and for reducing any potentially progressive features of this disorder.
Only eight people in the world have been diagnosed with CFZS with MYMK mutations, in part, because it hasn’t been readily recognized. Now that researchers have identified the genomic cause underlying the syndrome, it can be added to the diagnostic gene panels for congenital myopathies. This will improve the speed and accuracy of diagnosis and add to the understanding of the spectrum of disease severity and outcome, Dr. Manoli said.

The National Human Genome Research Institute (NHGRI)
www.genome.gov/27568961/2017-news-release-nih-and-collaborators-identify-the-genomic-cause-for-careyfinemanziter-syndrome/

Leading rheumatologist and Feinstein Institute for Medical Research Professor Betty Diamond, MD, may have identified a protein as a cause for the adverse reaction of the immune system in patients suffering from lupus. A better understanding of how the immune system becomes overactive will help lead to more effective treatments for lupus and potentially other autoimmune diseases.
Lupus is an autoimmune disease that causes the immune system to lose the ability to differentiate between foreign agents and healthy tissue. It becomes hyperactive and attacks healthy tissue, causing inflammation and damage to joints, skin, and internal organs. Previous studies have shown that a polymorphism or variation in the gene PRDM1 is a risk factor for lupus. PRDM1 enacts the production of a protein called Blimp-1. In this study, Dr. Diamond and her team were looking to examine how Blimp-1 regulates the immune system.
"A healthy immune system is able to identify organisms that are not normally in the body and activate cells like T-Cells to attack them," said Dr. Diamond. "In the case of patients with an autoimmune disease like lupus, the immune system has started to identify healthy cells as something to target. Our study found that a low level of or no Blimp-1 protein in a particular cell type led to an increase in the protein CTSS which caused the immune system to identify healthy cells as something to attack – particularly in females."
In an animal model, Dr. Diamond’s team was able to show that females with reduced production of Blimp-1 caused an increase in CTSS, a protein that helps the immune system see microbes, or a microorganisms that causes disease. This resulted in an immune system which attacked healthy cells. Male animals with the reduced production of Blimp-1 showed no change in their immune system. Though more study is required to confirm that the risk gene PRDM1 could lead to a hyperactive immune system in human females, this is a significant discovery to better understanding the causes and potential treatments for lupus.

EurekAlert
www.eurekalert.org/pub_releases/2017-07/nh-fii071417.php

They discovered a previously unknown group of regulatory T cells linked to the disease and DNA features that affect patients’ response to treatment
A team of scientists and doctors from the SingHealth Duke-NUS Academic Medical Centre (AMC) has uncovered a new group of regulatory T (Treg) cells and DNA features associated with juvenile idiopathic arthritis (JIA), the most common form of arthritis among children under the age of 16. Their findings could potentially enhance diagnosis of the disease and prediction of therapy outcomes for improved treatment successes.
JIA is a disease of the immune system that causes inflammation leading to pain, stiffness and swelling in patients’ joints. It affects around one in 1,000 children in the world.
Juvenile arthritis has no cure and young patients can only alleviate pain or prevent joint deterioration through use of medication or therapy. In advancing care for JIA, researchers are keen to identify the culprit cells or genetic signatures behind the disease in order to tackle it.
In its first discovery, the SingHealth Duke-NUS AMC research team identified a previously unknown group of Treg cells that is associated with inflammation in JIA. Treg cells are a subset of white blood cells that regulate the body’s immune system. When the body has an imbalanced number of Treg cells, its immune tolerance can fail and experience autoimmune disorders such as arthritis.
The team found that the identified Treg cells play a role in JIA progression. During the active disease stage of JIA, these cells expand, grow in number, re-circulate through inflamed areas of patients’ body, and migrate to the connective tissue of patients’ joints. Additionally, a larger quantity of these cells can be found in JIA patients who cannot control arthritis inflammation and are unresponsive to therapy as compared to those who are.
"Clinicians could potentially use this novel group of cells as a marker to diagnose JIA in patients, as well as to predict or monitor patients’ responsiveness to therapy. Importantly, these cells are readily detectable in patients’ bloodstream, allowing for any clinical tests to be minimally invasive and pain-free for patients," said Professor Salvatore Albani, Director, SingHealth Translational Immunology and Inflammation Centre (STIIC), Professor, Duke-NUS Medical School and Senior Clinician Scientist, KK Women’s and Children’s Hospital (KKH), who is the principal investigator of the study.
 
2nd discovery: Patients’ DNA affects JIA treatment outcomes
Currently, only about one-third of JIA patients get better after medication or therapy, while the rest continue to see their condition flare up even after treatment.
To accurately predict treatment outcomes, the research team studied JIA patients’ treatment responses and found that epigenetics – or individuals’ DNA and the way each body uses its genes – determined one’s clinical "fate". In other words, the key is not in individuals’ genetic make-up but rather, in how their bodies employ genes. Even patients with identical genetic backgrounds could experience different clinical outcomes based on their DNA features that activate genes differently.
One of the research paper’s co-author, Associate Professor Thaschawee Arkachaisri, Head & Senior Consultant, Rheumatology and Immunology Service, KKH and Associate Professor, Duke-NUS, said "These discoveries could enable doctors to predict treatment responses and personalise treatment for patients. This is especially relevant for difficult JIA cases which may require more complex therapies, and is important to help save time and money, prevent treatment complications and ultimately, improve care outcomes."
The team’s findings are also relevant for adult rheumatoid arthritis, a similar autoimmune condition that affects one in 100 adults in the world.

EurekAlert
www.eurekalert.org/pub_releases/2017-07/s-ssp071317.php

Heart failure refers to a condition in which heart muscle becomes weakened over time, making it increasingly difficult for the heart to pump blood through the body like it should.
It’s a progressive disease that begins when the heart adapts to stressors—high blood pressure, coronary artery disease, or diabetes, for example—in order to work properly. These stressors can lead to dilated cardiomyopathy, in which the heart’s left ventricle (pumping chamber) stretches, enlarges, and becomes thinner. Eventually, the heart cannot return to its normal shape, thus worsening its ability to pump blood and potentially leading to irregular heartbeats, blood clots, or even sudden death.
Researchers know that changes in gene expression occur during cardiomyopathy, but it remains unclear whether these changes are due to declining heart function or whether these changes are part of the progression to heart failure. A better understanding of the role transcription co-factors—proteins that are key to the regulation and expression of genes—could provide important clues into how heart failure develops.
Duane HallIn a new study, University of Iowa Health Care researchers report on the role of a protein—part of a large group of transcription co-factors called the Mediator complex—in regulating gene expression in heart muscle cells.
“A key question is how does the heart go from a normal state to a failing one after undergoing stress in some manner?” says Duane Hall, PhD, research assistant professor of internal medicine in the UI Carver College of Medicine and lead author of the study.
“It’s known that many genes are expressed during heart failure that are representative of a developing heart, so in these instances the heart may be trying to re-install developmental programs in order to adapt to those pressures,” adds Chad Grueter, PhD, assistant professor of internal medicine in the UI Carver College of Medicine and senior author of the study. “But we don’t fully understand how that transcriptional gene regulation happens, so we looked at how gene expression occurs through this Mediator complex.”
Grueter, Hall, and colleagues examined heart tissue samples from patients with heart failure and saw that levels of the protein Cdk8 in heart muscle cells were elevated. Knowing that Cdk8 is part of the Mediator complex and is involved in regulating the expression of thousands of genes, the researchers then over-expressed the protein in mouse heart cells. The increase in Cdk8 levels resulted in declining heart function and heart failure in these mice.
When the researchers examined the heart cells of the mice before a decrease in heart function was detectable, they found that more than 3,400 genes already were expressed with a profile similar to that of human heart muscle cells with dilated cardiomyopathy and heart failure.
Chad Greuter“Other studies have looked at tweaking the contraction and metabolism in heart cells as a possible cure for heart failure,” Hall says. “Our study is one of the first to show that something in the cell nucleus is capable by itself of inducing the structural changes that occur in heart failure.”
The study results suggest that modifying gene expression may provide a path to preventive treatments for heart failure.
“In terms of disease progression, heart failure is the end stage. Our study suggests that the transition, or ‘switch,’ from a stressed, enlarged heart to a failing heart is key,” Grueter says. “Looking ahead, hopefully we’ll be able to test whether a drug can block that switch from occurring.”

Carver College of Medicine
medicine.uiowa.edu/content/ui-study-examines-altered-gene-expression-heart-failure

Houston Methodist cancer researchers are now closer to creating a blood test that can identify breast cancer patients who are at increased risk for developing brain metastasis, and also monitor disease progression and response to therapy in real time.
The discovery of identifying a distinct group of cells in the bloodstream of patients who have breast cancer brain metastases could lead to the creation of more sensitive screening tools.
A proof-of-concept study led by Dario Marchetti, Ph.D., detected a distinct group of circulating tumour cells (CTCs) associated with brain metastasis. The finding brings cancer researchers closer to understanding how the “seeds” of metastatic disease can thrive in breast cancer patients and cause it to spread to the brain.
“Our research confirmed that CTCs in breast cancer brain metastases are distinct from other circulating tumour cells. Moreover, unlocking the mystery of how these seeds of metastatic disease survive and thrive over a period of years, sometimes decades, is an enigma in cancer,” said Marchetti, senior author and director of the Biomarker Research Program at Houston Methodist Research Institute. “Now we can take this information and develop a more sensitive screening tool to detect metastatic cancer in the blood, possibly even before metastasis is radiologically detectable by MRI.”
Magnetic resonance imaging is the accepted standard-of-care to diagnose breast cancer brain metastasis (BCBM) in patients. However, in most cases, by the time MRI detects the metastatic mass, the cancer has progressed to a stage where few curative treatment options are available, leading to poor overall survival. According to extensive clinical studies, approximately 20 percent of breast cancer patients will develop brain metastasis over their lifetime, and, in general, metastatic disease to the brain is estimated to become the number one cancer killer within the next decade.
“Our lab is the first in this field to perform a comprehensive report of patient-derived circulating tumour cells at the gene expression level, so we now have a clearer picture of the signalling pathways that allows them to establish brain metastases. By comparing the whole genome expression patterns of CTCs isolated from patient blood samples diagnosed with or without BCBM, we uncovered a 126 gene-signature that is specific to these brain metastatic CTCs,” said Debasish Boral, Ph.D., the paper’s first author and a research associate with the Biomarker Research Program at Houston Methodist Research Institute.
This research builds on a 2015 research paper where Marchetti’s lab isolated four distinct circulating tumour cell subsets that were implicated in breast cancer cell dormancy. Viable breast cancer cells can remain dormant in the patients’ bone marrow or other organs like the brain, lungs and liver, even decades after a primary tumour is surgically removed. These scattered cells are often undetectable by traditional clinical tools, making it nearly impossible to detect and treat metastatic disease while still amenable to therapy.
The Houston Methodist researchers are now focused on broadening the study patient population, with the end goal of transforming this information into the development of two kinds of non-invasive liquid biopsies that could be used by treating physicians: a screening method to predict brain metastasis before the disease is detectable by current diagnostic standards (MRI); and another to monitor treatment efficacy in real-time in those patients diagnosed with brain metastasis.

Houston Methodist Hospital
www.houstonmethodist.org/newsroom/Researchers-working-on-blood-test-to-detect-brain-metastases-while-still-treatable