Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study finds new gene mutations that lead to enlarged brain size, cancer, autism, epilepsy

02.07.2012
Researchers shed light on molecular cause of childhood’s worst conditions as first step toward developing more effective treatments

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.

Additional Resources

"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!
Further information:
http://www.seattlechildrens.org

More articles from Health and Medicine:

nachricht When wheels and heads are spinning - DFG research project on motion sickness in automated driving
22.05.2019 | Technische Universität Berlin

nachricht A new approach to targeting cancer cells
20.05.2019 | University of California - Riverside

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The geometry of an electron determined for the first time

Physicists at the University of Basel are able to show for the first time how a single electron looks in an artificial atom. A newly developed method enables them to show the probability of an electron being present in a space. This allows improved control of electron spins, which could serve as the smallest information unit in a future quantum computer. The experiments were published in Physical Review Letters and the related theory in Physical Review B.

The spin of an electron is a promising candidate for use as the smallest information unit (qubit) of a quantum computer. Controlling and switching this spin or...

Im Focus: Self-repairing batteries

UTokyo engineers develop a way to create high-capacity long-life batteries

Engineers at the University of Tokyo continually pioneer new ways to improve battery technology. Professor Atsuo Yamada and his team recently developed a...

Im Focus: Quantum Cloud Computing with Self-Check

With a quantum coprocessor in the cloud, physicists from Innsbruck, Austria, open the door to the simulation of previously unsolvable problems in chemistry, materials research or high-energy physics. The research groups led by Rainer Blatt and Peter Zoller report in the journal Nature how they simulated particle physics phenomena on 20 quantum bits and how the quantum simulator self-verified the result for the first time.

Many scientists are currently working on investigating how quantum advantage can be exploited on hardware already available today. Three years ago, physicists...

Im Focus: Accelerating quantum technologies with materials processing at the atomic scale

'Quantum technologies' utilise the unique phenomena of quantum superposition and entanglement to encode and process information, with potentially profound benefits to a wide range of information technologies from communications to sensing and computing.

However a major challenge in developing these technologies is that the quantum phenomena are very fragile, and only a handful of physical systems have been...

Im Focus: A step towards probabilistic computing

Working group led by physicist Professor Ulrich Nowak at the University of Konstanz, in collaboration with a team of physicists from Johannes Gutenberg University Mainz, demonstrates how skyrmions can be used for the computer concepts of the future

When it comes to performing a calculation destined to arrive at an exact result, humans are hopelessly inferior to the computer. In other areas, humans are...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

 
Latest News

Plumbene, graphene's latest cousin, realized on the 'nano water cube'

23.05.2019 | Materials Sciences

New flatland material: Physicists obtain quasi-2D gold

23.05.2019 | Materials Sciences

New Boost for ToCoTronics

23.05.2019 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>