Researchers Identify Three Novel Mutations in Mitochondrial Myopathy Patients

A recent study added new mutations to the short list of mutations identified within the MT-PT gene, which are known to cause mitochondrial myopathy. The study, led by Steven Hardy, PhD, from Newcastle University in England, is titled “Pathogenic mtDna Mutations Causing Mitochondrial Myopathy: The Need For Muscle Biopsy,” and was published in the journal American Academy of Neurology.

Mitochondrial diseases are often caused by mutations in the mitochondrial DNA (mtDNA), which affect mitochondrial function and, consequently, the generation of energy that powers most cell functions. Mitochondrial myopathy refers to a subgroup of mitochondrial diseases characterized by symptoms of neuromuscular disease.

The MT-PT gene encodes the mt-tRNA^Pro (tRNA is a molecule with a major role in protein synthesis within the cell) and, to date, only five mutations in this gene were associated with the development of mitochondrial myopathy.

The five patients included in the study presented myopathic symptoms, such as ptosis (drooping or falling of the upper eyelid) with more or less progressive paralysis of the ocular external muscles, proximal myopathy, and marked perceived fatigue. During the study, muscle biopsies allowed the detection of signs of mitochondrial defects in all patients, such as a marked degree of muscle fibers deficient in cytochrome c oxidase (COX) and reduced levels of both complex I and complex IV proteins (two important proteins for the process of energy production in mitochondria) in the muscle. According to the authors, this observation “was strongly suggestive of a defect in mitochondrial translation and entirely in keeping with a mt-tRNA mutation.”

To verify whether these signs were associated with mutations in the MT-PT gene, the authors sequenced the whole mitochondrial DNA, a technique that allows the detection of DNA mutations.

The results showed that all patients carried a mutation in the MT-PT gene. However, although patients 1 and 3 carried mutations previously identified (mutations m.15975T.C and m.16002T.C, respectively), patients 2, 4 and 5 presented novel mutations (mutations m.15998A.T, m.16015T.C, and m.16021_16022del, respectively).

The authors also observed that, whereas patients 1, 2, and 3 expressed their MT-TP mutations only in the muscle, strongly indicative of a de novo mutation (not inherited from the progenitors), the other two showed a pattern of hierarchical segregation, similar to other mtDNA mutations. In addition, given that mtDNA is inherited from the mother, maternal samples from the patients carrying the novel mutations (2, 4, and 5) were analyzed, but only patient 4 showed maternal inheritance of the mutation.

According to the authors, “only one of the previous studies demonstrated maternal inheritance of the MT-TP mutation, with 4 of the remaining studies also reporting apparent or likely de novo mutational events.”

Researchers also observed that the mutation load correlated with the degree of COX-deficient muscle fibers, which suggests that these mutations were indeed the cause of myopathy. This confirmation was only possible due to the analysis of muscle biopsies from the patients.

The authors emphasized that although some mutations have been reported previously, functional studies were not undertaken to confirm pathogenicity; therefore, muscle biopsies are “an ongoing requirement to access pathologically relevant tissue — skeletal muscle — to support the investigation and diagnosis of patients with mitochondrial myopathy.”

The team concluded that the results highlight “the importance of MT-TP mutations as a cause of mitochondrial muscle disease and the requirement to study clinically relevant tissue.”