Scientists have only recently begun to speculate that what’s referred to as “junk” DNA – the 96 percent of the human genome that doesn’t encode for proteins and previously seemed to have no useful purpose – is present in the genome for an important reason. But it wasn’t clear what the reason was. Now, researchers at the University of California, San Diego (UCSD) School of Medicine have discovered one important function of so-called junk DNA.
Genes, which make up about four percent of the genome, encode for proteins, “the building blocks of life.” An international collaboration of scientists led by Michael G. Rosenfeld, M.D., Howard Hughes Medical Investigator and UCSD professor of medicine, found that some of the remaining 96 percent of genomic material might be important in the formation of boundaries that help properly organize these building blocks. Their work will be published in the July 13 issue of the journal Science.
“Some of the ‘junk’ DNA might be considered ‘punctuation marks’ – commas and periods that help make sense of the coding portion of the genome,” said first author Victoria Lunyak, Ph.D., assistant research scientist at UCSD.
In mice, as in humans, only about 4 percent of the genome encodes for protein function; the remainder, or “junk” DNA, represents repetitive and non-coding sequences. The research team studied a repeated genomic sequence called SINE B2, which is located on the growth hormone gene locus, the gene related to the aging process and longevity. The scientists were surprised to find that SINE B2 sequence is critical to formation of the functional domain boundaries for this locus.
Functional domains are stretches of DNA within the genome that contain all the regulatory signals and other information necessary to activate or repress a particular gene. Each domain is an entity unto itself that is defined, or bracketed, by a boundary, much as words in a sentence are bracketed by punctuation marks. The researchers’ data suggest that repeated genomic sequences might be a widely used strategy used in mammals to organize functional domains.
“Without boundary elements, the coding portion of the genome is like a long, run-on sequence of words without punctuation,” said Rosenfeld.
Decoding the information written in “junk” DNA could open new areas of medical research, particularly in the area of gene therapy. Scientists may find that transferring encoding genes into a patient, without also transferring the surrounding genomic sequences which give structure or meaning to these genes, would render gene therapy ineffective.
Contributors to the paper include Lluis Montoliu, Rosa Roy and Angel Garcia-Díaz of the Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología in Madrid, Spain; Christopher K. Glass, M.D., Ph.D., UCSD Department of Cellular and Molecular Medicine; Esperanza Núñez, Gratien G. Prefontaine, Bong-Gun Ju, Kenneth A. Ohgi, Kasey Hutt, Xiaoyan Zhu and Yun Yung, Howard Hughes Medical Institute, Department of Molecular Medicine, UCSD School of Medicine; and Thorsten Cramer, Division of Endocrinology, UCSD Department of Medicine.
The research was funded in part by the Howard Hughes Medical Institute and the National Institutes of Health.
Contact: Debra Kain
University of California – San Diego
Contact: Erin Doonan
In the vast majority of Parkinson’s disease (PD) patients, the disorder arises not because of a genetic defect, but because some external insult triggers the death of dopamine-producing neurons. Now, researchers have reported progress in understanding the mechanism underlying that death, which they say suggests a new treatment pathway.
In both mice and human patients, the researchers have found evidence that neurons die because of a crippling of a particular protective enzyme that eliminates potentially damaging “reactive oxygen species” normally generated in the cell’s power plants, called mitochondria.
David Park, of the Ottawa Health Research Institute, and colleagues published their findings in the July 5, 2007 issue of the journal Neuron, published by Cell Press.
The researchers studied the mechanism of PD using a mouse model of the disease, in which a mitochondria-affecting toxin called MPTP is used to produce Parkinson’s-like brain pathology. In earlier studies, they had found that MPTP activates protein-snipping enzymes called calpains in mitochondria. They also found evidence that calpains, in turn, activate a cellular switch called Cdk5. The question, however, was how this abnormal activation ultimately kills neurons.
In their new studies, the researchers analyzed neurons to determine that Cdk5 regulates yet another enzyme called Prx2. This enzyme is known as a peroxidase and acts to render harmless the chemically active reactive oxygen species that are produced inside mitochondria in the process of generating energy for the cell.
Specifically, the researchers found that treating neurons with MPTP activates Cdk5 to switch off Prx2. What’s more, they found that activating Prx2 in MPTP-treated mice prevented the loss of dopamine-producing neurons. And they experimentally demonstrated that the action of Cdk5 on Prx2 “plays a pivotal role” in the neuronal damage from MPTP.
Importantly, the researchers discovered evidence that the loss of Prx2 activity also plays a role in human PD. They found reduced Prx2 activity in brain tissue from PD patients.
“These findings provide a mechanistic link of how a mitochondrial damaging agent, through calpain-mediated Cdk5 activation and downregulation of an important antioxidant enzyme, can increase oxidative load, leading ultimately to death,” concluded the scientists.
“Taken together, our findings suggest that strategies to modulate Prx2 activity serve as beneficial targets for treatment of PD,” they concluded. “This is of particular importance since Cdk5 is thought to have normal beneficial roles in neurons and modulating a relevant downstream target rather than Cdk5 directly may be a better therapeutic strategy with regard to this pathway.”
The researchers include Dianbo Qu, Juliet Rashidian, Matthew P. Mount, Hossein Aleyasin, Mohammad Parsanejad, Arman Lira, Emdadul Haque, Yi Zhang, Steve Callaghan, Mireille Daigle, Maxime W.C. Rousseaux, Ruth S. Slack, Paul R. Albert, John M. Woulfe, and David S. Park of University of Ottawa, Ottawa, Ontario, Canada; Inez Vincent of University of British Columbia, Vancouver, British Columbia, Canada.
This work was partially supported by the Parkinson’s Disease Foundation and the Parkinson’s Society of Canada (D.Q.) and the Heart and Stroke Foundation (J.R., H.A.) and by funds from the Canadian Institutes of Health Research, the Parkinson’s Society Canada, the Parkinson’s Disease Foundation, the Parkinson’s Research Consortium, the US army, and the Heart and Stroke Foundation of Ontario (D.S.P.).
Qu et al.: “Role of Cdk5-Mediated Phosphorylation of Prx2 in MPTP Toxicity and Parkinson’s Disease.” Publishing in Neuron 55, 37–52, July 5, 2007. DOI 10.1016/j.neuron.2007.05.033. http://www.neuron.org.
Contact: Emily Butler
Kennedy Krieger Institute
Researchers at the Kennedy Krieger Institute recognize children with autism earlier than ever before, paving the way for earlier intervention and improved outcomes
(Baltimore, MD) — In a study published today in the Archives of General Psychiatry, researchers from the Kennedy Krieger Institute in Baltimore, Maryland found that autism can be diagnosed at close to one year of age, which is the earliest the disorder has ever been diagnosed. The study, which evaluated social and communication development in autism spectrum disorders (ASD) from 14 to 36 months of age, revealed that approximately half of all children with autism can be diagnosed around the first birthday. The remaining half will be diagnosed later, and their development may unfold very differently than children whose ASD is diagnosable around the first birthday. Early diagnosis of the disorder allows for early intervention, which can make a major difference in helping children with autism reach their full potential.
Researchers examined social and communication development in infants at high and low risk for ASD starting at 14 months of age and ending at 30 or 36 months (a small minority of the children exited the study at 30 months). Half of the children with a final diagnosis of ASD made at 30 or 36 months of age had been diagnosed with the disorder at 14 months, and the other half were diagnosed after 14 months. Through repeated observation and the use of standardized tests of development, researchers identified, for the first time, disruptions in social, communication and play development that were indicative of ASD in 14-month olds. Multiple signs indicating these developmental disruptions appear simultaneously in children with the disorder.
Dr. Rebecca Landa, lead study author and director of Kennedy Krieger’s Center for Autism and Related Disorders, and her colleagues identified the following signs of developmental disruptions for which parents and pediatricians should be watching:
Abnormalities in initiating communication with others: Rather than requesting help to open a jar of bubbles through gestures and vocalizations paired with eye contact, a child with ASD may struggle to open it themselves or fuss, often without looking at the nearby person.
Compromised ability to initiate and respond to opportunities to share experiences with others: Children with ASD infrequently monitor other people’s focus of attention. Therefore, a child with ASD will miss cues that are important for shared engagement with others, and miss opportunities for learning as well as for initiating communication about a shared topic of interest. For example, if a parent looks at a stuffed animal across the room, the child with ASD often does not follow the gaze and also look at the stuffed animal. Nor does this child often initiate communication with others. In contrast, children with typical development would observe the parent’s shift in gaze, look at the same object, and share in an exchange with the parent about the object of mutual focus. During engagement, children have many prolonged opportunities to learn new words and new ways to play with toys while having an emotionally satisfying experience with their parent.
Irregularities when playing with toys: Instead of using a toy as it is meant to be used, such as picking up a toy fork and pretending to eat with it, children with ASD may repeatedly pick the fork up and drop it down, tap it on the table, or perform another unusual act with the toy.
Significantly reduced variety of sounds, words and gestures used to communicate: Compared to typically developing children, children with ASD have a much smaller inventory of sounds, words and gestures that they use to communicate with others.
“For a toddler with autism, only a limited set of circumstances – like when they see a favorite toy, or when they are tossed in the air – will lead to fleeting social engagement,” said Landa. “The fact that we can identify this at such a young age is extremely exciting, because it gives us an opportunity to diagnose children with ASD very early on when intervention may have a great impact on development.”
The current study reveals that autism often involves a progression, with the disorder claiming or presenting itself between 14 and 24 months of age. Some children with only mild delays at 14 months of age could go on to be diagnosed with ASD. Landa and her colleagues observed distinct differences in the developmental paths, or trajectories, of children with early versus later diagnosis of ASD. While some children developed very slowly and displayed social and communication abnormalities associated with ASD at 14 months of age, others showed only mild delays with a gradual onset of autism symptoms, culminating in the diagnosis of ASD by 36 months.
If parents suspect something is wrong with their child’s development, or that their child is losing skills during their first few years of life, they should talk to their pediatrician or another developmental expert. This and other autism studies suggest that the “wait and see” method, which is often recommended to concerned parents, could lead to missed opportunities for early intervention during this time period.
“What’s most exciting about these important advancements in autism diagnosis is that ongoing intervention research leads us to believe it is most effective and least costly when provided to younger children,” said Dr. Gary Goldstein, President and CEO of the Kennedy Krieger Institute. “When a child goes undiagnosed until five or six years old, there is a tremendous loss of potential for intervention that can make a marked difference in that child’s outcome.”
While there are currently no standardized, published criteria for diagnosing children with autism at or around one year of age, Landa’s goal is to develop these criteria based on this and other autism studies currently underway at the Kennedy Krieger Institute. Landa and her colleagues at the Institute plan on releasing preliminary diagnostic criteria for very young children with autism in an upcoming report.
Participants in the current study included infants at high risk for ASD (siblings of children with autism, n=107) and low risk for ASD (no family history of autism, n=18). Standardized tests of development and play-based assessment tools were used to evaluate social interaction, communication and play behaviors in both groups at 14, 18 and 24 months of age. Researchers assigned diagnostic impressions at every age, indicating whether there were clinically significant signs of delay or impairment. After their last evaluation at 30 or 36 months, each participant was then given a final diagnostic classification of ASD, non-ASD impairment, or no impairment. The ASD group was further divided into an Early ASD diagnosis group and a Later ASD diagnosis group based on whether they were given a diagnosis of ASD at 14 or 24 months.
Autism spectrum disorders (ASD) is the nation’s fastest growing developmental disorder, with current incidence rates estimated at 1 in 150 children. This year more children will be diagnosed with autism than AIDS, diabetes and cancer combined, yet profound gaps remain in our understanding of both the causes and cures of the disorder. Continued research and education about developmental disruptions in individuals with ASD is crucial, as early detection and intervention can lead to improved outcomes in individuals with ASD.
About the Kennedy Krieger Institute
Internationally recognized for improving the lives of children and adolescents with disorders and injuries of the brain and spinal cord, the Kennedy Krieger Institute in Baltimore, MD serves more than 13,000 individuals each year through inpatient and outpatient clinics, home and community services and school-based programs. Kennedy Krieger provides a wide range of services for children with developmental concerns mild to severe, and is home to a team of investigators who are contributing to the understanding of how disorders develop while pioneering new interventions and earlier diagnosis. For more information on Kennedy Krieger Institute, visit http://www.kennedykrieger.org.
Contact: Holly Korschun
A new genetic test targeting the most common types of muscular dystrophy–those caused by mutations in the dystrophin gene–is far quicker with greater accuracy and sensitivity than existing tests. It can be used to confirm clinical diagnoses, to test female family members who may be carriers, and to perform prenatal testing.
The test was developed by Michael Zwick, PhD, and Madhuri Hegde, PhD, assistant professors in the Department of Human Genetics and the Emory Genetics Laboratory in the Emory University School of Medicine.
Muscular dystrophy includes more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. Some forms are seen in infancy or childhood, while others may not appear until middle age or later. Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy and primarily affects boys. It is caused by absence of dystrophin, an important muscle protein involved in maintaining the strength of muscle fibers.
According to the National Institute of Neurodegenerative Diseases and Stroke (NINDS), DMD onset is between 3 and 5 years, with rapid progression. Most boys are unable to walk by age 12 and later need a respirator to breathe. Girls in these families have a 50 percent chance of inheriting and passing the defective gene to their children. Becker muscular dystrophy, which is similar to Duchenne but less severe, results from faulty or not enough dystrophin.
As currently implemented the new test, called EmArray Dystrophin, detects 99 percent of mutations in the dystrophin gene including deletions, duplications and point mutations.
The EmArray Dystrophin test uses a new kind of microarray technology that contains the entire sequence of the dystrophin gene, the largest known gene in humans, on a chip the size of a microscope slide. The test initially detects deletions and duplications, then microarray-based resequencing is used to rapidly identify subtle genetic variations that may cause muscular dystrophy.
The EmArray Dystrophin test confirms clinical diagnosis of Duchenne and Becker muscular dystrophy in a male and characterizes the type and size of the mutation. Women with a family history of Duchenne or Becker who are at risk to be carriers can be tested, then, if found to be carriers, can have prenatal testing.
“Previously, access to prenatal testing was limited for some women when the affected male relative was not available for testing. The EmArray Dystrophin test greatly improves access to prenatal and carrier testing for women without the need to test a male relative, in a rapid timeframe,” according to Vanessa Rangel Miller, MS. In addition to improved testing, the Emory Genetics Laboratory, Parent Project Muscular Dystrophy, leading researchers and clinicians are working together to develop a database for mutations and clinical data.
“Our new genetic test, along with new therapies currently in clinical trials, is a very positive development for muscular dystrophy patients and their families,” says Dr. Hegde.
In the last five years DMD research has accelerated, resulting in more knowledge about the role of the dystrophin gene and an increased understanding about what happens to a muscle cell lacking the dystrophin protein. Researchers around the world are investigating a number of different treatment strategies, all with the goal of slowing or stopping muscle degeneration. Several clinical trials are underway and many others are in development, including testing of an oral medication intended to circumvent mutations in the dystrophin gene and increase normal gene expression.
According to Dr. Hegde, about 13 percent of mutations in the dystrophin gene are nonsense mutations–point mutations in a sequence of DNA that can result in mistakes in gene expression and nonfunctional proteins. New data published online in the current edition of the journal Nature show that PTC124, an investigational new drug designed to bypass dystrophin nonsense mutations and restore a functional protein, was effective in a preclinical (animal) model of Duchenne muscular dystrophy (DMD). (www.clinicaltrials.gov).
Other treatment for symptoms associated with muscular dystrophy may include physical therapy, respiratory therapy, speech therapy, orthopedic appliances and corrective orthopedic surgery. Drug therapy may include corticosteroids, anticonvulsants, immunosuppressants and antibiotics.
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