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Genomics reveals gene for deadly childhood disease
By Adam Marcus

Scientists have identified the gene that causes a form of Leigh syndrome, a fatal childhood disease that is twenty times more prevalent in the Saguenay-Lac Saint-Jean region of Quebec than elsewhere. A test is being developed to screen individuals in the region for mutations in the gene.

The gene, LRPPRC, produces a protein in mitochondria, the organelles that power cells. Children born with two mutant copies of LRPPRC do not produce enough energy and have severe metabolic problems. Most do not survive to adolescence.


To pinpoint the gene, the researchers screened part of chromosome 2, where the gene was thought to reside. They then profiled the activity of 30 possible candidates. One gene in particular, LRPPRC, behaved as though it were involved in producing energy.

LRPPRC codes for a protein that may help mitochondria assemble their energy-generating chemical machinery. "It's probably not affecting the entire mitochondrion but a portion" of the organelle, says Vamsi Mootha, of the Whitehead Institute/MIT Center for Genome Research in Cambridge, Massachusetts, and a member of the project team.

Other forms of Leigh syndrome may be caused by mutations in related genes, he adds. The research is described in Proceedings of the National Academy of Sciences.

The French Canadian form of Leigh syndrome—or human cytochrome c oxidase deficiency—can involve delayed development, weak muscles, liver and neurological problems, and dangerous buildups of lactic acid in blood. These buildups are the body's response to a lack of energy, which can result from infections or stress.

Finding the mutations behind French Canadian Leigh syndrome could help doctors screen fetuses for the disorder. Quebec scientists are also exploring ways of testing prospective parents in Saguenay-Lac Saint-Jean for the errors.

"The carrier rate of this [trait] in the region is about five percent," says Grant Mitchell, a medical geneticist at Ste.-Justine Hospital in Montreal and a collaborator on the research.

Leigh syndrome generally affects about one in 40,000 births. But in Saguenay-Lac Saint-Jean, it occurs in one in every 2,000 births, or the same rate as cystic fibrosis.

Mitchell says the high rate of LRPPRC mutations in Quebec is a remnant of the early settlement of the area by a small number of French colonists. The deadly error was either already present in this group when they arrived in the New World, or arose spontaneously and spread through the expanding population.

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Mootha, V. K. et al. Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc Natl Acad Sci USA 100, 605-610 (January 14, 2002).

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