Findings of a recent genetic study on developmental brain disorders may be the “tip of an iceberg” revealing factors involved with a number of congenital diseases, according to UC Irvine researchers.
The study is the first to find that mutations in the structural proteins in brain cells – beta-actin – are linked to disorders such as deafness and dystonia, a debilitating neural disease, and further suggests that genetic variants of these proteins may play a wider role with inherited human diseases. Study results appeared in the June issue of the American Journal of Human Genetics.
The findings give vital clues to the basis of some developmental disorders and make early diagnosis possible for diseases such as dystonia, allowing for greater treatment opportunities, said Dr. Vincent Procaccio of UCI’s Center for Molecular and Mitochondrial Medicine and Genetics and lead author, though the study does not point to potential therapies.
“These types of actin proteins are prevalent throughout the body and play a key role in processes that are an essential part of development,” said Procaccio, who is also an assistant professor of pediatrics. “To find that these mutations are involved with brain disorders seems to be the tip of an iceberg. Since beta-actin is involved with many developmental cell functions, it would appear that its genetic variants can be involved with a number of other congenital disorders.”
Procaccio and his colleagues studied brain tissue samples from deceased twins who had a number of developmental disabilities including dystonia, a neurological disorder that causes twisting or jerking movements in parts of the body. Genetic analysis revealed mutations in the beta-actin gene. These mutations affected protein conformation, which would not allow beta-actin to bind with ATP – the chemical fuel synthesized by mitochondria that give a cell its energy.
Beta-actin is a structural protein that helps form the cytoskeleton – a cell’s skeleton that gives it structure and strength. Unable to receive fuel, the mutated beta-actin proteins break down, ultimately damaging and destroying the cell. In the brain, this leads to the neural tissue damage related to congenital neurological disorders like dystonia.
Taking this information, Procaccio and his fellow researchers are working to demonstrate that beta-actin mutations are a common cause of neurological disorders. They are currently analyzing several DNA samples from patients to identify additional abnormalities. In addition, they are investigating the cellular and biophysical abnormalities resulting from beta-actin mutations, which will serve as a basis to identify other mutations and disease phenotypes arising from genetic abnormalities of beta-actin proteins.
“Ultimately, we hope to prove that the identification of genetic abnormalities of the beta-actin are likely to explain the causes of a spectrum of disease phenotypes, including congenital malformation syndromes and other inherited degenerative diseases, that are presently poorly understood,” he said.
Study co-authors are Antonio Davila and Richard Jimenez of UCI; Gloria Salazar, Shoichiro Ono, Melanie Styers, Victor Faundez, Marla Gearing, Jorge Juncos, Claire-Anne Gutekunst and Bruce Wainer of Emory University in Atlanta; Estelle Sontag and Jean Marie Sontag of University of Texas Southwest Medical Center in Dallas; and Germana Meroni and Bianca Fontanella of the Telethon Institute of Genetics and Medicine in Naples, Italy. The National Institutes of Health supported the study.
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