MUTATION ASSOCIATED WITH CLEFT PALATE IDENTIFIED

Scientists studying birth defects in humans and purebred dogs have identified an association between cleft lip and cleft palate -- conditions that occur when the lip and mouth fail to form properly during pregnancy -- and a mutation in the ADAMTS20 gene. Their findings were presented at the American Society of Human Genetics (ASHG) 2014 Annual Meeting in San Diego.

"These results have potential implications for both human and animal health, by improving our understanding of what causes these birth defects in both species," said Zena Wolf, BS, a graduate student at the University of California, Davis School of Veterinary Medicine.

In both humans and dogs, cleft lip and cleft palate occur naturally with varying degrees of severity, and can be caused by various genetic and environmental factors. Since purebred dogs breed only with each other, there is less genetic variation to consider, making cleft lip and cleft palate easier to understand in these populations, Ms. Wolf explained.

From previous studies, the researchers knew that a mutation in the dog genes DLX5and DLX6, which are involved in face and skull development, explained 12 of 22 cases of cleft palate. However, a mutation in the corresponding human genes accounted for just one of 30 cases in the study sample.

To search for additional genes that may be involved, Ms. Wolf and colleagues performed a genome-wide association study (GWAS), a study that compares the genomes of dogs with cleft lip and cleft palate to those of dogs without it. They found that the conditions were associated with a mutation in the gene ADAMTS20 that caused the protein it encodes to be shortened by 75 percent. Previous studies had shown that ADAMTS20 is involved in the development and shaping of the palate, but no specific mutations that occur in nature had been identified. A similar GWAS in people with cleft lip and cleft palate suggested that mutations in the human version of the ADAMTS20 gene may also increase the risk of these conditions.

"Cleft lip and cleft palate are complex conditions in people, and the canine model offers a simpler approach to study them," Ms. Wolf said. "Not only does this research help people, but it helps dogs, too," she added.

The study was conducted by scientists at the University of California, Davis, along with collaborators at the University of Pittsburgh, the University of Iowa, and the University of Sydney.

Future directions include searching for additional genes that may be associated with cleft lip and cleft palate, and extending the research to other breeds of dogs, such as Labrador Retrievers and Whippets.

EARLY SIGN OF PANCREATIC CANCER IDENTIFIED

Scientists at Dana-Farber Cancer Institute, the Massachusetts Institute of Technology, and other institutions have discovered a sign of the early development of pancreatic cancer – an upsurge in certain amino acids that occurs before the disease is diagnosed and symptoms appear. The research is being published online today by the journal Nature Medicine.

Although the increase isn’t large enough to be the basis of a new test for early detection of the disease, the findings will help researchers better understand how pancreatic cancer affects the rest of the body, particularly how it can trigger the sometimes deadly muscle-wasting disease known as cachexia.

“Most people with pancreatic ductal adenocarcinoma (PDAC) [by far the most common form of cancreatic cancer] are diagnosed after the disease has reached an advanced stage, and many die within a year of diagnosis,” said Brian Wolpin, MD, MPH, of Dana-Farber, co-senior author of the new study with Matthew Vander Heiden, MD, PhD, of MIT and Dana-Farber. “Detecting the disease earlier in its development may improve our ability to treat it successfully. In this study, we asked whether PDAC produces metabolic changes – changes in the way the body uses energy and nutrients – that can be detected before the disease is diagnosed.”

The researchers utilized blood samples collected years earlier from 1,500 people participating in large health-tracking studies. They analyzed the samples for more than 100 different metabolites – substances produced by the metabolic process – and compared the results from participants who had gone on to develop pancreatic cancer and those who had not.

“We found that higher levels of branched chain amino acids were present in people who went on to develop pancreatic cancer compared to those who did not develop the disease,” Wolpin said. (Branched chain amino acids are one family of amino acids, the building blocks of proteins.) The amount of time that would elapse before those individuals were diagnosed with pancreatic cancer ranged from two to 25 years, although the highest risk was in the several years before diagnosis, the researchers found.

“These findings led us to hypothesize that the increase in branched chain amino acids is due to the presence of an early pancreatic tumor,” Wolpin remarked. This theory was confirmed in laboratory experiments performed by Vander Heiden’s group at the Koch Institute for Integrative Cancer Research at MIT. Their experiments showed that mice with newly formed pancreatic tumors had above-normal blood levels of these amino acids.

The researchers found the increase was due to a breakdown of muscle tissue, which caused branched amino acids to be released into the bloodstream. This process is similar to what occurs in patients with cancer cachexia. “What was surprising about our results was that it appears the breakdown of muscle protein begins much earlier in the disease process than previously appreciated,” noted Vander Heiden.

The findings provide an important lead to scientists studying how pancreatic tumors interact with patients’ normal tissues, the authors say. According to Vander Heiden, this work provides a glimpse into how pancreatic cancer changes the way the rest of the body handles nutrients. “This work has the potential to spur progress in detecting pancreatic tumors earlier and identifying new treatment strategies for those with the disease,” he remarks.

BALDNESS HUMAN HAIRLESS GENE IDENTIFIED

It's not a hair-brained idea: A new research report appearing in the April 2014 issue of The FASEB Journal explains why people with a rare balding condition called "atrichia with papular lesions" lose their hair, and it identifies a strategy for reversing this hair loss. Specifically the report shows for the first time that the "human hairless gene" imparts an essential role in hair biology by regulating a subset of other hair genes. This newly discovered molecular function likely explains why mutations in the hairless gene contribute to the pathogenesis of atrichia with papular lesions. In addition, this gene also has also been shown to function as a tumor suppressor gene in the skin, raising hope for developing new approaches in the treatment of skin disorders and/or some cancers

Identification of hairless as a histone demethylase may shed new insights into its mechanism of action in regulating skin and hair disorders," said Angela M. Christiano, Ph.D., FACMG, a researcher involved in the work from the Departments of Dermatology and Genetics and Development at the Columbia University College of Physicians and Surgeons in New York, NY. "The genes identified in this study could open up new opportunities for developing mechanism-driven approaches for future prevention or treatment of skin diseases including skin cancer and rare forms of hair loss."

To make their discovery, Christiano and colleagues defined the histone demethylase function of the human hairless gene, both in vitro and using cultured human cells. When the hairless protein was mixed with specific histone substrates under defined reaction conditions, the hairless protein causes a reduction in the level of methylation modification of the histone substrates. Similarly, upon expression of normal hairless protein, but not a mutant form of the hairless protein, researchers observed a drastic loss of histone methylation in human cells. This suggests that this may be the "on/off" switch for hair growth as well as a promising target for some types of skin disease.

"Humans have tried everything to keep their hair, from snake oils to spray-on bald spot solutions," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "Now, however, we are finally getting to the root of the problem to manipulate one of the switches that control hair growth."