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New Gene Associated With Mitochondrial Disease Adds To Diagnostic Capability

September 3, 2013

The mitochondria are the powerhouses of the cell, converting energy into usable forms. When a child is born with a gene defect that results in dysfunctional mitochondria, the results can be devastating, causing physical and cognitive disability and often death.

Using genome-wide sequencing along with personalized functional genomics, researchers led by those at Baylor College of Medicine have identified mutations in a gene called FBXL4 revealing it as a novel cause of primary mitochondrial disease, a finding that may speed diagnosis in other families. A report on their work appears online today in the American Journal of Human Genetics.

Unravel mystery

“The number one reason a child is referred to a genetic clinic is developmental delay, which is often part of mitochondrial disease,” said Dr. Penelope E. Bonnen, assistant professor of molecular and human genetics at BCM and the first author of the report. “It is important for us to be able to accurately diagnose children who have a mitochondrial disease and exclude those children who do not.”

“There are more than 1,000 genes that can cause mitochondrial disease,” she said. “It is a rich pool to be able to reach into and every time know that you might discover something new and further unravel the mystery of mitochondrial disease.”

Exome sequencing, the technique of sequencing the protein-coding portion of the human genome, sped this finding along, said Bonnen.

In this case, the three children in whom the gene mutation was identified came from Saudi Arabia but were not related. One of the patients came directly to Houston and was seen at Texas Children’s Hospital by Dr. Brett Graham, a pediatric geneticist who helped treat his condition. The other two children were evaluated diagnostically in the United Kingdom. They came to the attention of Dr. Robert Taylor, director of the Wellcome Trust Centre for Mitochondrial Research at The Medical School of Newcastle University in the UK, and a corresponding author of the report with Bonnen.

In each case, exome sequencing identified a mutation in the FBXL4 gene, a different mutation for each child. In two cases, the mutation abruptly cut the protein short (a truncating mutation), which was a devastating problem. Both children died before the age of 2. In the other child, the mutation was a single base pair. While the child was seriously affected, he is still alive.

Personalized medicine

To further prove that the mutation and the gene were involved, Bonnen took the finding into her laboratory. There she took the patients’ “sick” cells and put a healthy copy of the gene into the cells in the laboratory. When she did that, it “rescued” or corrected the mitochondrial defect.

“That’s why we call it personalized medicine,” she said. “Specifically, we study patient’s cells and determine on an individualized basis this is what causes the patient’s clinical problem.” Gene therapy is not currently possible for these children and may never be used to solve the problem, she cautioned.

However, just giving parents an answer can be helpful, she said.

Diagnostic odyssey

“These families go through a diagnostic odyssey with endless tests,” she said. “They can go years without receiving a molecular diagnosis that pinpoints the genetic or genomic problem involved.” In some cases, families are told the problem is a mitochondrial disease, even when it is not.

“Even when a genetic finding does not translate into a treatment, families take some solace in knowing the diagnosis. They can finally end the search,” she said.

She emphasized that the research was a truly international event with close collaboration with Taylor and his team in the United Kingdom and the clinician/geneticists in Saudi Arabia.

She speculates that the gene may turn out to be a more common cause of mitochondrial disease. She said she and Taylor are already beginning to identify more patients with the mutation and none of them are from Saudi Arabia.

Others who took part in this work include: Arnaud Besse, Ping Wu, Taraka Donti, Lee-Jun Wong, William J. Craigen, Brett H. Graham and Kenneth L. Scott, all of BCM;John W. Yarham, Eve M. Simcos, LangpingHe and Robert McFarland, all of Wellcome Trust Centre for Mitochondrial Research at Newcastle upon Tyne, UK; Eissa A. Faqueih, Ali Mohammad Al-Asmari and Mohammad A.M. Saleh, allof Children’s Hospital, King Fahad Medical City, Saudia Arabia; Wafaa Eyaid and Alrukban Hadeel of King Abdulaziz Medical City in Riyadh, Saudi Arabia; Frances Smith and Shu Yau of Guy’s and St.Thomas’ Serco Pathology, Guy’s Hospital in London, UK; Satmi Miwa of Newcastle University in Newcastle upon Tyne, UK; and Khaled K. Abu-Amero of the Ophthalmic Genetics Laboratory at the College of Medicine at King Saud University in Riyadh.

Funding for this work came from the Texas Norman Hackerman Advanced Research Program (NHARP) under Grant No. [THECB] 02006; the Cytometry and Cell Sorting Core at BCM with funding from the National Institutes of Health (AI036211, CA125123, and RR024574), a Medical Research Council (UK) Centenary Early Career Award, an HEFCE/DoH Clinical Senior Lecturer Award, a Wellcome Trust Strategic Award (096919/Z/11/Z) ), the MRC Centre for Neuromuscular Diseases (G0601943), the Lily Foundation, and the UK NHS Specialist Commissioners that funds the “Rare Mitochondrial Disorders of Adults and Children’ Diagnostic Service in Newcastle upon Tyne.

For more information on research at Baylor College of Medicine, please go to From the Lab.

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Source: BCM



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