Gene Mutations Associated With Enlarged Brain Size, Disorders

Lawrence LeBlond for – Your Universe Online

At least three genetic mutations found in the human brain have been linked to enlarged brain size (megalencephaly) and a number of disorders, including cancer, epilepsy and autism, according to new research led by Seattle Children´s Research Institute.

The mutations were found in the genes AKT3, PIK3R2 and PIK3CA. The mutations were also linked to vascular disorders and skin growth disorders, said the researchers. The study, published in the online edition of the journal Nature Genetics on June 24, offers important implications for the future of medicine through the research findings.

Study leaders, geneticist William Dobyns, MD, and Jean-Baptiste Rivière, PhD, discovered through their research additional proof that the genetic makeup of a person is not completely determined at the moment of conception. The new evidence ties in with previous research that recognized that genetic changes can occur after conception, although considered quite rare.

The researchers also discovered the genetic causes of these human diseases, including developmental disorders, may also directly lead to new possibilities for treatment.

AKT3, PIK3R2 and PIK3CA are found in all humans, but only when they are mutated do they lead to the diseases and disorders. PIK3CA is known as a cancer-related gene, and appears to make cancer more aggressive. Boston Children´s Hospital researchers recently found a common link between the PIK3CA gene and a rare condition known as CLOVES syndrome.

James Olson, MD, PhD, a pediatric cancer expert at Seattle Children’s and Fred Hutchinson Cancer Research Center acknowledged the two decades-worth of work that led to the findings.

“This study represents ideal integration of clinical medicine and cutting-edge genomics,” said Olson, who was not involved in the latest research. “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.”

He noted that the team did an excellent job by “deep sequencing exceptionally rare familial cases and unrelated cases to identify the culprit pathway.” He further noted that the three genes all encode core components of the phosphatidylinositol-3-kinase/AKT pathway, the “culprit pathway,” as referenced by his work.

The research team hope the findings lead to new treatments for children with these chronic diseases within the coming 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 Dobyns. “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.”

Next on tap for the team: delving more deeply into the findings, aiming 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,” explained Rivière. “This research truly helps advance the concept of personalized medicine.”

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