A research team led by Seattle Children's Research Institute has discovered new gene mutations associated with markedly enlarged brain size, or megalencephaly. Mutations in three genes, AKT3, PIK3R2 and PIK3CA, were also found to be associated with a constellation of disorders including cancer, hydrocephalus, epilepsy, autism, vascular anomalies and skin growth disorders.
The study, "De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes," was published online June 24 in Nature Genetics.
The discovery offers several important lessons and hope for the future in medicine. First, the research team discovered additional proof that the genetic make-up of a person is not completely determined at the moment of conception. Researchers previously recognized that genetic changes may occur after conception, but this was believed to be quite rare. Second, discovery of the genetic causes of these human diseases, including developmental disorders, may also lead directly to new possibilities for treatment.
AKT3, PIK3R2 and PIK3CA are present in all humans, but mutations in the genes are what lead to conditions including megalencephaly, cancer and other disorders. PIK3CA is a known cancer-related gene, and appears able to make cancer more aggressive. Scientists at Boston Children's Hospital recently published similar findings related to PIK3CA and a rare condition known as CLOVES syndrome in the American Journal of Human Genetics.
Physician researcher James Olson, MD, PhD, a pediatric cancer expert at Seattle Children's and Fred Hutchinson Cancer Research Center who was not affiliated with the study, acknowledged the two decades-worth of work that led to the findings. "This study represents ideal integration of clinical medicine and cutting-edge genomics," he said. "I hope and believe that the research will establish a foundation for successfully using drugs that were originally developed to treat cancer in a way that helps normalize intellectual and physical development of affected children. The team 'knocked it out of the park' by deep sequencing exceptionally rare familial cases and unrelated cases to identify the culprit pathway." The genes— AKT3, PIK3R2 and PIK3CA—all encode core components of the phosphatidylinositol-3-kinase (P13K)/AKT pathway, the "culprit pathway" referenced by Olson.
The research provides a first, critical step in solving the mystery behind chronic childhood conditions and diseases. At the bedside, children with these conditions could see new treatments in the next decade. "This is a huge finding that provides not only new insight for certain brain malformations, but also, and more importantly, provides clues for what to look for in less severe cases and in conditions that affect many children," said William Dobyns, MD, a geneticist at Seattle Children's Research Institute. "Kids with cancer, for example, do not have a brain malformation, but they may have subtle growth features that haven't yet been identified. Physicians and researchers can now take an additional look at these genes in the search for underlying causes and answers."
Researchers at Seattle Children's Research Institute will now delve more deeply into the findings, with an aim to uncover even more about the potential medical implications for children. "Based on what we've found, we believe that we can eventually reduce the burden of and need for surgery for kids with hydrocephalus and change the way we treat other conditions, including cancer, autism and epilepsy," said Jean-Baptiste Rivière, PhD, at Seattle Children's Research Institute. "This research truly helps advance the concept of personalized medicine."
Drs. Dobyns, Rivière and team made this discovery through exome sequencing, a strategy used to selectively sequence the coding regions of the genome as an inexpensive but effective alternative to whole genome sequencing. An exome is the most functionally relevant part of a genome, and is most likely to contribute to the phenotype, or observed traits and characteristics, of an organism.
Background On Researchers
Seattle Children's Research Institute conducted this study in collaboration with teams from University of Washington Genome Sciences Department, FORGE (Finding of Rare Disease Genes) Canada Consortium, Cedars Sinai Medical Center and University of Sussex.
Dr. Dobyns, who is also a UW professor of pediatrics, is a renowned researcher whose life-long work has been to try to identify the causes of children's developmental brain disorders such as megalencephaly. He discovered the first known chromosome abnormality associated with lissencephaly (Miller-Dieker syndrome) while still in training in child neurology at Texas Children's Hospital in 1983. That research led, 10 years later, to the discovery by Dobyns and others of the first lissencephaly gene known as LIS1.
Dr. Rivière is supported by a Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research. As a lead researcher in the Dobyns lab, he also identified two new genes that cause Baraitser-Winter syndrome, a rare smooth brain malformation.
Co-authors on this study include: Jean-Baptiste Rivière, PhD, Banting Postdoctoral Fellow at Seattle Children's Research Institute; Judith St-Onge, Seattle Children's Research Institute; Christopher Sullivan, Seattle Children's Research Institute; Thomas Ward, Seattle Children's Research Institute; Ghayda Mirzaa, MD, University of Chicago; Brian O'Roak, PhD, University of Washington; Jay Shendure, MD, PhD, University of Washington; Mark O'Driscoll, PhD, University of Sussex; John Graham, MD, ScD, Cedars Sinai Medical Center; Kym Boycott, MD, PhD, University of Ottawa, Children's Hospital of Eastern Ontario; and many other physicians and scientists from North America and Europe.
"De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes": http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.2331.html
"Researchers find gene for 9-year-old girl's 1-in-a-million disease", CommonHealth/WBUR, May 2012: http://commonhealth.wbur.org/2012/05/life-of-riley-gene-cloves
"Cause of rare growth disease discovered", MedicalXpress, June 2012: http://medicalxpress.com/news/2012-06-rare-growth-disease.html
"Gene Mutations Cause Massive Brain Asymmetry", UC San Diego Health System, June 2012: http://health.ucsd.edu/news/releases/Pages/2012-25-hemimegalencephaly.aspx
About Seattle Children's Research Institute
At the forefront of pediatric medical research, Seattle Children's Research Institute is setting new standards in pediatric care and finding new cures for childhood diseases. Internationally recognized scientists and physicians at the Research Institute are advancing new discoveries in cancer, genetics, immunology, pathology, infectious disease, injury prevention and bioethics. With Seattle Children's Hospital and Seattle Children's Hospital Foundation, the Research Institute brings together the best minds in pediatric research to provide patients with the best care possible. Children's serves as the primary teaching, clinical and research site for the Department of Pediatrics at the University of Washington School of Medicine, which consistently ranks as one of the best pediatric departments in the country. For more information, visit http://www.seattlechildrens.org/research.
Mary Guiden | EurekAlert!
Why might reading make myopic?
18.07.2018 | Universitätsklinikum Tübingen
Unique brain 'fingerprint' can predict drug effectiveness
11.07.2018 | McGill University
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
18.07.2018 | Materials Sciences
18.07.2018 | Life Sciences
18.07.2018 | Health and Medicine