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In an advance illustrating the power of genomic information, an international team of researchers today announced it has identified a gene that causes Leigh Syndrome, French Canadian type (LSFC), a fatal inherited disorder affecting 1 in 2000 live births each year in the Saguenay-Lac St Jean region of Quebec. The paper appears in the January 14 issue of the journal Proceedings of the National Academy of Sciences.

The findings will have immediate clinical implications for families in the Saguenay-Lac St-Jean region in the Quebec province in Canada, where the disorder is common and is associated with high infant and childhood mortality. Identification of the gene will enable physicians to provide carrier testing and improved prenatal diagnostic options to members of this community, whose only way of knowing now is after the child is born.

The findings also illustrate the power and promise of integrative genomic approaches to finding disease. Armed with a clue that the culprit is related to mitochondrial function, the scientists searched for leads in three types of genomic datasets聴the human genome sequence, expression profiles (data from DNA chips that measure activity of thousands of genes simultaneously), and proteomics data. When information gathered from the three platforms were integrated, a single gene, LRPPRC, stood out as the clear suspect. The team then tested this gene in patients, parents, and controls and identified two mutations that cause the disease. These findings provided definitive proof that the LRPPRC gene is responsible for LSFC.

"Genomic information is changing the way we tackle disease," says Eric Lander, Director of the Whitehead/MIT Center for Genome Research. "Over the next decade, scientists will increasingly be able to use powerful global tools and integrative strategies to accelerate disease-gene discovery, even for complex, common diseases like diabetes and heart disease."

The work was done by an international team of scientists at the Whitehead Institute/MIT Center for Genome Research in Cambridge, MA; Genome Quebec Innovation Centre, McGill University Health Centre in Montreal; MDS Proteomics in Odense, Denmark; Montreal Genome Centre, McGill University Health Centre in Montreal; Hospital for Sick Children in Toronto; Service de Genetique Medicale, Hopital Sainte-Justine in Montreal; and the Department of Pediatrics and Clinical Research Unit, Chicoutimi, Canada. (See paper for a full listing of authors.),
"It is gratifying to finally find the gene for this devastating childhood disease and provide this community tangible diagnostic tools," says John Rioux, who directs a human genetics team at the Whitehead/MIT Center for Genome Research and has been working on the problem since he left French Canada seven years ago. "We have heard so much about the power of genomics, and to see it applied in a way that has immediate clinical implications is truly rewarding."

"I am thrilled and excited by these findings," says Vamsi Mootha, postdoctoral fellow at the Whitehead/MIT Center for Genome Research. "It is amazing to be doing research in an era where the detective work of finding disease-genes has become a matter of downloading data from publicly available databases."

"This work truly captures the spirit of international collaboration, and of the value of interdisciplinary approaches to tackle the genetic underpinnings of disease," says Thomas Hudson, Director of the Montreal Genome Centre in Canada. Hudson is also an alumnus of the Whitehead/MIT Center for Genome Research and a native of the SLSJ region. "We also are enormously grateful to the patients and their families for their ongoing cooperation and support."

Leigh Syndrome, French Canadian type (LSFC)

LSFC is an autosomal recessive disorder that affects 1 in 2000 live births in the SLSJ region (the same incidence rate as Cystic Fibrosis). It results when a child inherits two copies of a defective gene, one from each unaffected parent. The parents are otherwise healthy carriers who have one defective copy and a normal copy that protects them against the disease. Without symptoms or genetic tests, parents have no way of knowing if they are carriers until it's too late聴after they give birth to a child with the disease. One in 23 inhabitants of this region are estimated to be carriers.

Scientists have known that this genetic defect of unknown origin causes malfunctioning in mitochondria (tiny energy factories in the cell) that results in defects in energy metabolism and symptoms of mental retardation and a dangerous accumulation of toxic lactic acid in the blood that leads to coma. These episodes can occur anytime between 6 months to 11 years of age. Often this metabolic crisis is the first indication that an outwardly happy child has the disease. One third of the children don't survive the first crisis and those who do survive end up having a second or third crisis that is fatal.

Physicians in the SLSJ region first began noticing the disease in the 1990s and began to see a pattern that suggested this was a genetic disease. In 1993, Charles Morin, a pediatrician who had treated many affected children, showed in collaboration with Brian Robinson of the Toronto Hospital for Sick Children that the symptoms were caused by a deficiency in an enzyme called cytochrome c oxidase (COX) that prevents proper energy metabolism. But the genetic defect underlying this deficiency still remained unknown.

Scientists then began to conduct family studies to identify the gene involved. In 1997, Morin, Robinson, and Whitehead's Rioux began a collaboration to search for the gene. In 2001, the group led by Whitehead narrowed the search for the gene to a region on the short arm of chromosome 2, but an analysis of the known genes in that region found that none of the genes were involved in mitochondria or appeared to be connected to COX.

Enter Genomics

Around the same time, Vamsi Mootha, a young physician postdoctoral fellow of Lander and an expert on mitochondrial biology, asked to tackle the problem by applying the new tools of genomics.

Using a three-pronged approach, Mootha begain by searching the latest sequence data on the mouse and human genomes. He collected comprehensive information on all the known and predicted genes in the region on chromosome 2 where the gene was thought to lie. He found 30 distinct genes whose function was not known.
Mootha and his colleagues then used publicly available expression profile data聴data from DNA chips that allows researchers to study which of thousands of genes are on or off in any given cell. Such expression profiles generate signature patterns that are unique to cell types. The researchers screened the profiles to see which of the genes of unknown function had the expression signature, or DNA fingerprint, of a mitochondrial gene. In less than one week, they found one gene, LRPPRC, that had a striking signature of a mitochondrial gene. They then studied mouse data, and the same gene popped up again.

In the meantime, the Montreal Genome Centre in McGill University was also working on the genome sequences. Pierre LePage, working in Hudson's laboratory independently identified the same gene, corroborating the suspicion that LRPPRC was indeed the responsible gene.

"We were really excited, but wanted more experimental proof that this was indeed the culprit," says Mootha, who was collaborating with MDS Proteomics in Denmark to compile a comprehensive list of all proteins in mitochondria, using mass spectrometry. The COX team then studied to see if any of the DNA sequences in the region on chromosome 2 was associated with a protein from this dataset of mitochondrial proteins. They found that the LRPPRC gene made the list.

For final clinical proof that LRPPRC is responsible for LSFC, the scientists sequenced the gene in two patients, one parent, and one unaffected individual and found a single DNA letter change in the gene that followed an autosomal recessive inheritance pattern. They then tested this in a larger population of patients and found that 21 out of 22 patients had two copies of the gene with this mutation and one patient had a copy with this mutation and a second copy with a different mutation. The identification of the two mutations in LRPPRC provided definitive genetic proof that this gene is responsible for LSFC.

What's Next?

The identification of the LRPPRC mutations will have immediate clinical implications for patients and their families in SLSJ region.
"A diagnostic test that can detect carriers and provide improved prenatal diagnostic options will be a boon to the members of our community," says Pierre Lavoie, president of the Cytochrome c Oxidase Association of the Saguenay-Lac St Jean region, famous triathlete, and parent of children who died of the disease. "Without such a test, parents didn't know if they carried the defective gene until it was too late."

Scientists hope that the same strategy can work to identify the genes for the other diseases, including common diseases such as diabetes.

The project is funded by grants from Association de L'acidose Lactique du Saguenay-Lac St-Jean, National Centre of Excellence for Genetic, Genome Quebec, and Canadian Institutes for Health Research, a Howard Hughes Medical Institute Postdoctoral Fellowship, and a grant from Affymetrix/Bristol Myers Squibb/Millennium Pharmaceuticals.