SerRS Mutations Seen as Cause of CMT in 3 Unrelated Families
2 variants newly identified, supporting SerRs screening if cause unknown
Mutations in the SerRS gene — which is critical for protein production — were identified as the cause of Charcot-Marie-Tooth disease (CMT) in three families in China, a study reported.
Researchers found that two newly-identified SerRS mutations likely acted to disrupt the process by which proteins are produced from their messenger RNA (mRNA) template, which derives from DNA.
This work “expands the known causative genes associated with CMT and provides an in-depth investigation of the identified SerRS variants,” the researchers wrote, adding that “SerRS variants should be screened and considered for CMT patients lacking genetic diagnosis.”
The study, “Heterozygous Seryl-tRNA synthetase 1 variants cause Charcot-Marie-Tooth disease,” was published in the Annals of Neurology.
People with CMT often lack an established genetic diagnosis
CMT encompasses a group inherited conditions affecting the peripheral nervous system, or the network of nerves that relay movement and sensory information from the brain and spinal cord to the rest of the body.
While mutations in more than 100 genes have been found to cause different types of CMT, many patients don’t have mutations in these genes, and their genetic diagnosis remains undetermined.
Mutations in several of the 37 genes that provide instructions to produce enzymes called aminoacyl-tRNA synthetases (ARSs) have been identified as a cause for some types of CMT — being the largest family of proteins to be implicated in the disease.
ARSs are key for the process of protein production. Normally, genetic information on DNA is first translated into an mRNA molecule that subsequently serves as a template for protein production.
Proteins are assembled in a sort of factory, called the ribosome, and specific RNA structures called transfer RNAs (tRNAs) carry the appropriate amino acid, a protein’s building blocks, to the ribosome where the mRNA message is converted into a protein.
These tRNAs serve as a link between the mRNA and the growing string of amino acids that form the final protein.
ARSs, also called tRNA ligases, are enzymes responsible for binding tRNAs to their respective amino acids, in a process called aminoacylation. However, the mechanisms by which ARS gene mutations cause disease are not well-established.
Now, researchers in China described the cases of three unrelated families affected by CMT due to mutations in SeRS, the gene that codes for an ARS called seryl-tRNA synthetase 1 (SerRS1).
The families were identified in two previous observational studies (NCT04010188 and NCT04967716) aimed at better understanding the natural history and genetics of CMT in affected families in China.
Of the 839 CMT families who participated in the studies, three were found to have SeRS mutations, yielding a frequency of 0.358%. Of these three families, all 16 affected family members and 14 unaffected members underwent genetic testing.
One SeRS mutation, called p.Gln239Leu, was identified in two of the families, and a different variant, p.Ser396Phe, was found in the third family. Both mutations were heterozygous, meaning that affected family members had a copy of the mutated gene inherited from one parent and a healthy copy inherited from the other.
Both mutations were absent in genetic databases of healthy people, and were located in a SeRS region that is key for aminoacylation, suggesting they were likely to cause disease. They also were predicted to be functionally harmful to the resulting SerRS1 protein in computer algorithms.
The 16 patients, with a mean age at disease onset of 17 (range, 10–30 years), had similar symptoms, including slowly progressive muscle wasting and weakness, and reduced reflexes. Ten also had hand or foot deformities. All retained walking ability, but two unrelated patients required a cane.
Tests of nerve activity, or electrophysiology, revealed abnormalities in the peripheral nerves involved in mediating movement. These also showed completely absent signals in the nerves that mediate sensation in all eight patients with available sensory nerve data.
Of the eight people with CMT neuropathy scores, which are used to assess disability, four had mild disability and the other four had moderate disability.
2 new mutations may relate to ‘toxic gain-of-function mechanism’
Notably, three patients from the same family “manifested only mild [nerve damage] symptoms … but revealed a predominant absence of sensory nerve conduction,” the researchers wrote.
“Accordingly, we propose that electrophysical examination should be a priority to confirm the [disease-causing properties] of genetic variants identified in ARSs genes,” they added.
Further studies were conducted to learn more about the effects of the two newly-identified SeRS mutations. Patient-derived cells grown in the lab showed significantly lower SerRS1 activity and impaired aminoacylation compared with cells derived from healthy people.
These defects appeared to be driven by a “toxic gain-of-function mechanism,” characterized by the formation of abnormal clusters of mutated and healthy SerRS1 that affect overall function, the team wrote.
Additional experiments demonstrated that protein production was impaired as a consequence of the mutations. Researchers noted that further studies are needed to better understand the mechanisms underlying the effects of SerRS mutations in CMT.
Previously identified CMT-causing mutations in ARS genes yield a wide range of symptoms and not all of them directly affect aminoacylation, suggesting “a shared but complex mechanism underlying the disease,” the researchers wrote.
Overall, “this study extends our understanding of the molecular mechanisms behind ARS-related CMT,” the team concluded.
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