Severe Mitochondrial Disease Traced to Rare Mutation in OPA1 Gene

A newly found mutation in the OPA1 gene has been linked to a mitochondrial condition involving general brain dysfunction, thickening of the heart muscle, and degeneration of the optic nerve. The report, published in the Journal of Medical Genetics, is the first to describe the severe disease consequences of the mutation.

Infants with defects in mitochondrial energy production often have the typical features of general brain dysfunction — encephalopathy — and abnormally thick heart muscle. Numerous underlying genetic defects can cause the condition, and mutations in both genomic and mitochondrial DNA have been associated with it. The study by Israeli researchers, from the Emek Medical Center, is a case report of two sisters presenting the condition.

An analysis revealed that the children had an overall decrease in all the mitochondrial energy producing complexes, spurring a genetic investigation. The parents were cousins, so a genome-wide homozygosity mapping technique was used to identify rare mutations in the children. Since finding rare recessive disorders in people who are not related is a difficult task, the method, when used in related individuals, makes use of the fact that the patient likely has two identical copies of a faulty gene inherited from a common ancestor.

The team focused on mitochondria-related genes and found a mutation in OPA1, where a leucine aminoacid was replaced with an arginine in a region that is evolutionary conserved, and hence likely to be crucial for protein function.

According to the report, “Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation,“ the researchers investigated the protein levels of OPA1, and noted that the mutation led to substantially lower levels of the protein. In addition, mitochondrial DNA was largely depleted in muscle tissue biopsy. Using transmission electron microscopy, the team observed that mitochondria in the muscle tissue were enlarged, with incomplete fusion of the inner mitochondrial membrane.

OPA1 serves a multitude of functions in mitochondria, including the assembly and stability of the mitochondrial energy producing complexes and of mitochondrial DNA. OPA1 mutations are associated with dominant optic atrophy (DOA), a condition characterized by degeneration of the optic nerve. Reports of a more severe disease form affecting multiple organs, however, exist. While the mutation described in the study has not been previously reported, the results showed that OPA1 mutations can have more far-reaching consequences than optic nerve atrophy.