Mom's mitochondria may hold mutation.

Mom's mitochondria may hold mutation

Scientists discovered in the early 1960s that mitochondria, the power-generating stations inside clls, contain a few genes of their own. Now Emory University scientists in Atlanta have linked a specific defect in mitochondrial DNA to a rare form of blindness. The discovery confirms suspicions that tainted genes in these tiny power packs can indeed cause genetic defects and suggests a whole new mechanism for inherited diseases.

Several hundred mitochondria exist in the cytoplasm of each cell, their handful of genes distinct and separate from those packed on the chromosomes inside the cell nucleus. Altogether, the mitochondria contain about 0.3 percent of a cell's total DNA. These genes code for proteins vital to the production of adenosinetriphosphate (ATP), the key fuel used by cells. Unlike the DNA in the nucleus, which comes equally from the mother and father, the genes in the mitochondria come only from the mother.

Douglas C. Wallace and his colleagues discovered that people suffering Leber's hereditary optic neuropathy (LHON) have a defect in one mitochondrial gene that codes for a protein involved in the first step of ATP production. This defect results in the amino acid histidine being substituted for the amino acid arginine during the protein's synthesis, Wallace reported this week at the Short Course in Medical and Experimental Mammalian Genetics at the Jackson Laboratory in Bar Harbor, Maine, cosponsored by johns Hopkins University in Baltimore.

LHON results in optic nerve death and often causes blindness by age 20. Since mitochondria are passed on only by the mother, if she carries the defect, every one of her children will inherit it. Yet only a minority of people who inherit the defective gene go blind, Wallace notes.

"IT's clear this mutation, which is a very, very subtle mutation, predisposes you to the problem, but is not sufficient in and of itself to prove you're going to go blind," he says. "So we think there are other factors. Another interesting aspect of these patients is that there is a bias toward males going blind over females. That might be a cultural difference or there might be differential [cell] respiration rates in the sexes." He cites smoking and diet as possibl cultural factors.

Wallace and his colleagues found the genetic defect in nine of 11 LHON patients they studied, but failed to detect it in any of 45 controls. He says this could mean that more than one genetic defect predisposes people to the disease or, more likely, that the two people who did not have the protein problem were misdiagnosed as having LHON.

"The exciting thing ... is that we're now really finding the mutations that can explain this kind of phenomenon, and beginning to understand them at the biochemical level, to be able to develop diagnostic tools," Wallace says.

Researchers suspect several other rare genetic ailments stem from mitochondrial DNA defects. But Wallace suggests some cases of more common diseases also may result from genetic defects in the mitochondria. All cells require ATP to function, but some cells require more of the fuel than others. Evidence suggests different defective genes within the mitochondria will decrease ATP production to differing degrees, so some cells may work quite well with low ATP while others fail, Wallace says.

He speculates that some cases of heart, kidney an central nervous system failure, whose causes are now unknown, may one day prove the result of defective mitochondrial DNA.