Posts tagged birth defects
Articles and news from the latest research reports.
Clues to Fetal Alcohol Risk: Molecular switch promises new targets for diagnosis and therapy
Fetal alcohol syndrome is the leading preventable cause of developmental disorders in developed countries. And fetal alcohol spectrum disorder (FASD), a range of alcohol-related birth defects that includes fetal alcohol syndrome, is thought to affect as many as 1 in 100 children born in the United States.
Any amount of alcohol consumed by the mother during pregnancy poses a risk of FASD, a condition that can include the distinct pattern of facial features and growth retardation associated with fetal alcohol syndrome as well as intellectual disabilities, speech and language delays, and poor social skills. But drinking can have radically different outcomes for different women and their babies. While twin studies have suggested a genetic component to susceptibility to FASD, researchers have had little success identifying who is at greatest risk or what genes are at play.
Research from Harvard Medical School and Veterans Affairs Boston Healthcare System sheds new light on this question, identifying for the first time a signaling pathway that might determine genetic susceptibility for the development of FASD. The study was published online Feb. 19 in the journal Proceedings of the National Academy of Sciences.
“Our work points to candidate genes for FASD susceptibility and identifies a path for the rational development of drugs that prevent ethanol neurotoxicity,” said Michael Charness, chief of staff at VA Boston Healthcare System and HMS professor of neurology. “And importantly, identifying those mothers whose fetuses are most at risk could help providers better target intensive efforts at reducing drinking during pregnancy.”
The discovery also solves a riddle that had intrigued Charness and other researchers for nearly two decades. In 1996, Charness and colleagues discovered that alcohol disrupted the work of a human protein critical to fetal neural development—a major clue to the biological processes of FASD. The protein, L1, projects through the surface of a cell to help it adhere to its neighbors. When Charness and his team introduced the protein to a culture of mouse fibroblasts cells, L1 increased cell adhesion. Tellingly, the effect was erased in the presence of ethanol (beverage alcohol).
Charness and his team went on to develop multiple cell lines from that first culture, and that’s where they encountered the riddle: In some of those lines, alcohol disrupted L1’s adhesive effect, while in others it did not.
“How could it be possible that a cell that expresses L1 is completely sensitive to alcohol, and others that express it are completely insensitive?” asked Charness, who is also faculty associate dean for veterans hospital programs at HMS and assistant dean at Boston University School of Medicine.
Clearly, something else was affecting the protein’s sensitivity to alcohol — but what? Studies of twins provided one clue: Identical twins are more likely than fraternal twins to have the same diagnosis, positive or negative, for FASD. “That concordance suggests that there are modifying genes, susceptibility genes, that predispose to this condition,” Charness said.
The first detailed and complete picture of a protein complex that is tied to human birth defects as well as the progression of many forms of cancer has been obtained by an international team of researchers led by scientists with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab). Knowing the architecture of this protein, PRC2, for Polycomb Repressive Complex 2, should be a boon to its future use in the development of new and improved therapeutic drugs.
This is how a heart becomes a heart
A “synchronised dance” of thousands of genes generates a healthy heart, but one faux pas may result in congenital heart defects.
Congenital heart defects (CHD) are one of the most common birth abnormalities in the world. In Australia six babies are born with a heart disease every day and more than 32,000 children under the age of 18 live with a CHD, but a team of researchers at the Gladstone Institutes have found the genetic switches that translate as a functional heart.
Using next-generation DNA sequencing and stem cell technology, the researchers were able to decipher the genomic blueprint (the instruction manual) of a heart. The finding will help understand how certain CHDs such as holes in the heart (septal defects) are formed. “Congenital heart defects are the most common type of birth defects,” said Gladstone Senior Investigator Benoit Bruneau to UCFS news. “But how these defects develop at the genetic level has been difficult to pinpoint because research has focused on a small set of genes. Here, we approach heart formation with a wide-angle lens by looking at the entirety of the genetic material that gives heart cells their unique identity.”
The cellular cause of birth defects like cleft palates, missing teeth and problems with fingers and toes has been a tricky puzzle for scientists.
Professor Emily Bates and her biochemistry students at Brigham Young University studied an ion channel that regulates the electrical charge of a cell. In a new study published by the journal Development, they show that blocking this channel disrupts the work of a protein that is supposed to carry marching orders to the nucleus.
Without those instructions, cells don’t become what they were supposed to become – be that part of a palate, a tooth or a finger. Though there are various disorders that lead to birth defects, this newly discovered mechanism may be what some syndromes have in common.
Bates and her graduate student, Giri Dahal, now want to apply the findings toward the prevention of birth defects – particularly those caused by fetal alcohol syndrome and fetal alcohol spectrum disorder.
"What we think might be the case is that this is the target for a few similar disorders," Bates said. "The big thing that we have right now is that this ion channel is required for protein signaling, which means that developmental signaling pathways can sense the charge of a cell. And that’s exciting for a lot of different reasons."
For example, the new study might also have implications for the battle against cancer. With cancer, the problem is that cells are receiving a bad set of instructions that tells them to multiply and spread. If they can devise a way to block the ion channel, it may stop those cancerous instructions from getting through.
"This protein signaling pathway is the same one that tells cancer cells to metastasize," Bates said. "We’re planning to test a therapy to specifically block this channel in just the cells that we want to stop."
Imaging Study Sheds New Light on Alcohol-Related Birth Defects
A collaborative research effort by scientists at the University of North Carolina School of Medicine, Duke University, and University College of London in the UK, sheds new light on alcohol-related birth defects.
The project, led by Kathleen K. Sulik, PhD, a professor in the Department of Cell and Developmental Biology and the Bowles Center for Alcohol Studies at UNC, could help enhance how doctors diagnose birth defects caused by alcohol exposure in the womb. The findings also illustrate how the precise timing of that exposure could determine the specific kinds of defects.
“We now know that maternal alcohol use is the leading known and preventable cause of birth defects and mental disability in the United States,” Sulik said. “Alcohol’s effects can cause a range of cognitive, developmental and behavioral problems that typically become evident during childhood, and last a lifetime.”
Fetal alcohol syndrome (FAS) is at the severe end of fetal alcohol spectrum disorders (FASD). First described in 1972, FAS is recognized by a specific pattern of facial features: small eyelid openings, a smooth ridge on the upper lip (absence of a central groove, or philtrum), and a thin upper lip border.
In its full-blown state, FAS affects roughly 1 in 750 live births in the U.S. And while clinicians typically look for those classical facial features in making a diagnosis, within the broader classification of FASD “adverse outcomes vary considerably and most individuals don’t exhibit the facial characteristics that currently define FAS,” said the study’s lead author Robert J. Lipinski, PhD, a postdoctoral scientist in Sulik’s lab. “This study could expand the base of diagnostic criteria used by clinicians who suspect problems caused by maternal alcohol use.”
In their animal-based studies, the Sulik lab team has collaborated with co-author G. Allan Johnson, PhD and his group at Duke University’s Center for In Vivo Microscopy. Johnson, professor of radiology and physics, has developed new imaging tools with spatial resolution up to a million times higher than clinical magnetic resonance imaging (MRI). These include small bore tools suitable for imaging fetal mice that are only 15 mm long.
To quantify facial shape from MRI data, the study team turned to co-author Peter Hammond, a professor of computational biology at UCL’s Institute of Child Health, in London. Hammond invented powerful new techniques for 3D shape analysis that have already proven successful in objectively defining facial shape changes in humans.
In the study, described in the August 22, 2012 issue of the online journal PLOS ONE, Lipinski and Sulik treated one group of mice with alcohol on their seventh day of pregnancy, a time corresponding to the third week of pregnancy in humans. A second group of mice was treated just 36 hours later, approximating the fourth week of human pregnancy. The amount of alcohol given was large, “high doses that most women wouldn’t achieve unless they were alcoholic and had a tolerance for alcohol,” Sulik said.
Near the end of pregnancy, the fetuses were then imaged at Duke University. These 3D data sets showed individual brain regions, as well as accurate and detailed facial surfaces, from which Hammond and research assistant and co-author Michael Suttie performed shape analyses.
The team found that the earlier alcohol exposure time elicited the classic FAS facial features, including characteristic abnormalities of the upper lip and eyes. What they observed in fetuses exposed just 36 hours later, however, was a surprise. These mice exhibited unique and in some cases opposing facial patterns, such as shortened upper lip, a present philtrum, and the brain, instead of appearing too narrow in the front, appeared wide.
“Overall, the results of our studies show that alcohol can cause more than one pattern of birth defects, and that the type and extent of brain abnormalities—which are the most devastating manifestation of prenatal alcohol exposure—in some cases may be predicted by specific facial features,” Sulik said. “And, importantly, alcohol can cause tremendously devastating and permanent damage at a time in development when most women don’t recognize that they’re pregnant.”
Source: Newswise