Researchers have found that certain mutations in the mitochondrial genes, which alone don’t seem to cause disease, are sufficient to trigger Leber’s hereditary optic neuropathy (LHON) when combined.
Based on their findings, researchers defend a new approach for diagnosing LHON and perhaps other mitochondrial diseases, based on full DNA sequencing of the mitochondrial genome.
The study, “Peculiar combinations of individually non-pathogenic missense mitochondrial DNA variants cause low penetrance Leber’s hereditary optic neuropathy,” was published in the journal PLOS Genetics.
More than 90 percent of LHON cases result from mutations in the MT-ND1, MT-ND4 and MT-ND6 genes present in the mitochondrial DNA (mtDNA).
These disease-causing mutations are distinct from the mtDNA genetic variations found in the general population, which reflect biologic variability and are not considered to trigger disease. Not everyone with mutations in the LHON genes will develop the disease.
Some studies have shown that other genetic variants on a person’s mtDNA can enhance the disease-causing potential of the LHON mutations and increase the risk for developing the condition.
For example, a mutation in the MT-ND1 can act as an adaptive variant selected for high altitudes in Tibet, but it can also predispose people to LHON with other genetic backgrounds, such as the Chinese.
Therefore, it is important to identify the LHON-causing genetic mutations and distinguish them from the combined action of different variants.
A team of researchers examined peculiar LHON scenarios in four Italian families.
Sine family members displayed a clinical diagnosis of LHON and a clear pattern of maternal transmission. But none of them tested positive for the three most common LHON mutations.
After sequencing the entire mitochondrial genome, researchers found two unusual combinations of gene mutations carried by the families. One consisted of two mutations in the MT-ND6 gene, and the other included mutations in the MT-ND4L, MT-ND1, and the MT-ND6 genes.
Alone, these mutations fall into the category of normal and non-disease causing variations, but when combined they caused LHON in a few family members.
Since most individuals with the mutations did not develop LHON, these are believed to cause “low-penetrance” LHON.
When examining cells from patients, researchers found mild mitochondrial dysfunction, similar to that reported for the primary LHON mutations, but did not observe an increase in oxidative stress, characteristic of LHON.
Taken together, the study revealed the existence of multiple variants that cause LHON besides the known primary mutations associated with the disease.
The team defends new criteria for diagnosing LHON and perhaps other mitochondrial diseases, based on the entire sequencing of the mtDNA.
“Our study has profound implications for the diagnosis of LHON,” researchers wrote.
“For an accurate diagnosis of LHON and possibly of other mitochondrial diseases, the only approach that can disclose all possible causative sources is complete mitogenome sequencing,” they added.