Thursday, August 29, 2013

Study Discovers Gene that Causes Devastating Mitochondrial Diseases

MAYWOOD, Ill. - Researchers have identified a novel disease gene in which mutations cause rare but devastating genetic diseases known as mitochondrial disorders.

Nine rare disease-causing mutations of the gene, FBXL4, were found in nine affected children in seven families, including three siblings from the same family. An international team of researchers report the discovery in the Sept. 5, 2013, issue of the American Journal of Human Genetics, published online ahead of the print version.

The lead author is Xiaowu Gai, PhD, director of  the Center for Biomedical Informatics at Loyola University Chicago Stritch School of Medicine.

Mitochondrial diseases are caused by defects in mitochondria, the cell’s energy plants. Malfunctions in mitochondria lead to multisystemic defects in the brain, heart, muscles, kidney, and endocrine and respiratory systems. The many possible clinical symptoms include loss of motor control, muscle weakness, heart disease, diabetes, respiratory problems, seizures, vision and hearing problems, diabetes and developmental delays.

Mitochondrial diseases are caused by mutations in either mitochondrial DNA or in genes in the nucleus that encode for proteins that function in the mitochondria. Mitochondrial DNA is inherited from the mother. Thus, a child can inherit a mitochondrial disease either from the mother alone or from both parents carrying mutations in the same nuclear gene. Mitochondrial diseases affect between 1 in 4,000 and 1 in 5,000 people.

FBXL4 is a nuclear gene that encodes for a protein called F-Box and Leucine-Rich Repeat Protein 4. The study found that mutations of this gene lead to either truncated or altered forms of the protein. This results in cells having less mitochondrial DNA, decreased mitochondrial membrane potential and a faulty process in cell metabolism called oxidative phosphorylation. The study also proved that the FBXL4 protein is located exclusively in mitochondria, which was previously unrecognized.

While mutations in more than 100 genes have been linked to mitochondrial diseases, the new discovery adds another novel disease gene to the list. Consequently, genetic testing will enable more parents to discover the cause of their children’s mitochondrial diseases. “This knowledge will help give them the peace of mind that it was not something they did to cause the disease,” Gai said. More importantly, the discovery also will improve scientists’ understanding of mitochondrial diseases and potentially lead to new drugs to treat the disorders, Gai said.

The discovery began with an 8-year-old girl who had a mitochondrial disease known as Leigh syndrome. She has been seen by Dr. Marni J. Falk of The Children’s Hospital of Philadelphia, who is a co-senior author of the study. A battery of  genetic tests of the girl and her parents over the years all had failed to find any of the gene mutations previously known to cause mitochondrial diseases.

Gai and Falk used the high-performance computer cluster at Loyola’s Center for Biomedical Informatics to analyze billions of DNA sequences to identify the gene mutation in the child and her parents. The research team then reached out to other collaborators to see if any of their patients also had the FBXL4 mutation. Eight additional affected children in six unrelated families were found to also have disease-causing mutations in this gene.

The discovery is an example of  how Loyola’s Center for Biomedical Informatics is using computational approaches to address basic biomedical questions.

Isolating an unknown mutation can involve sequencing and analyzing a patient's entire genome, containing 6 billion base pairs (DNA letters). Powerful computational approaches and infrastructure are required to read and compare sequences of billions of DNA base pairs.

The study included collaborators from several research centers in the United States, Europe and the Middle East. In addition to Gai, the research team included co-first authors Daniele Ghezzi, Mark A. Johnson, Caroline A. Biagosch, Hanan E. Shamseldin and Tobias B. Haack and co-senior authors Peter Freisinger, Wolfgang Sperl, Holger Prokisch, Fowzan S. Alkuraya, Marni J. Falk and Massimo Zeviani.

About Loyola University Health System

Loyola University Health System (LUHS) is part of Trinity Health. Based in the western suburbs of Chicago, LUHS is a quaternary care system with a 61-acre main medical center campus, the 36-acre Gottlieb Memorial Hospital campus and more than 30 primary and specialty care facilities in Cook, Will and DuPage counties. Loyola University Medical Center’s campus is conveniently located in Maywood, 13 miles west of Chicago’s Loop and 8 miles east of Oak Brook, Ill. At the heart of the medical center campus is a 559-licensed-bed hospital that houses a Level 1 Trauma Center, a Burn Center and the Ronald McDonald® Children's Hospital of Loyola University Medical Center. Also on campus are the Cardinal Bernardin Cancer Center, Loyola Outpatient Center, Center for Heart & Vascular Medicine and Loyola Oral Health Center as well as Loyola University Chicago Stritch School of Medicine, Loyola University Chicago Marcella Niehoff School of Nursing and the Loyola Center for Fitness. Loyola's Gottlieb campus in Melrose Park includes the 255-licensed-bed community hospital, the Professional Office Building housing 150 private practice clinics, the Adult Day Care, the Gottlieb Center for Fitness, Loyola Center for Metabolic Surgery and Bariatric Care and the Loyola Cancer Care & Research at the Marjorie G. Weinberg Cancer Center at Melrose Park.

Trinity Health is a national Catholic health system with an enduring legacy and a steadfast mission to be a transforming and healing presence within the communities we serve. Trinity is committed to being a people-centered health care system that enables better health, better care and lower costs. Trinity Health has 88 hospitals and hundreds of continuing care facilities, home care agencies and outpatient centers in 21 states and 119,000 employees.