Scientists have discovered a link between a mutation in the CARS late-onset genetic and neurological disorders with symptoms, such as movement disorders, similar to those seen in patients with Parkinson’s disease.
The mutation, known as CARS E795V, has been identified as the cause of a neurological disease affecting nine people from four related families. The disease is characterized by mobility problems and signs of neurodegeneration. The mutation is inherited in an autosomal dominant manner, meaning that only one copy of the gene is enough to cause the disease.
“This research underscores the importance of genetic analysis in identifying the root causes of complex diseases and paves the way for future studies aimed at developing targeted therapies,” said a press release from BGI Genomics, which collaborated with researchers in China to produce the study.
The study, “Cysteinyl-tRNA synthetase mutation causes novel autosomal dominant inheritance of parkinsonism/spinocerebellar ataxia complexwas published in Bulletin of neuroscience.
Nine patients, aged 42 to 62 and from four different families, had features including difficulty walking, cerebellar ataxia (inability to coordinate balance, gait and movements of the eyes and extremities) and parkinsonism, an umbrella term for a range of diseases including Parkinson’s and others that cause symptoms such as tremors, muscle rigidity and slow movements.
Disease progression related to main symptoms
Eight patients also experienced pyramidal signs, or neurological symptoms that affect muscles under voluntary control, resulting in abnormal muscle tension after contraction, muscle weakness, and overactive body reflexes.
Disease progression was found to correlate with the severity of these core symptoms. Patients who had had the disease for more than eight years experienced worsening symptoms, with all requiring a wheelchair after eight years.
Symptoms that affected only some patients included peripheral neuropathy (damage to nerves outside the brain and spinal cord), cognitive impairment, erectile dysfunction, facial grimacing (involuntary distortion of facial expressions), and stridor, a whistling sound that occurs during breathing due to partial obstruction of the upper airway.
Four of the nine people affected underwent MRI scans of the brain, which identified varying degrees of neurodegeneration in regions of the brain, including black substancea key region of the brain affected by Parkinson’s disease.
Imaging analysis revealed a resemblance to features seen in multiple system atrophy, an atypical form of Parkinson’s disease. These features included iron accumulation in certain areas of the brain and decreased regional cerebral blood flow.
To find out the cause of the disease, researchers performed a genetic screen that detected the E795V mutation in the CARS The gene was found in all nine affected patients, but not in unaffected family members. No known mutations responsible for the disease related to spinocerebellar ataxias were found. Like Parkinson’s disease, this group of inherited neurological disorders causes a progressive loss of muscle control, coordination and balance.
THE CARS The gene is responsible for the production of the protein cysteinyl-tRNA synthetase (CARS), which plays a crucial role in regulating the incorporation of amino acids, fundamental components of proteins, during cell growth and differentiation processes.
A mutation in this gene would lead to structural alterations in the CARS protein, potentially affecting its function. The researchers validated these predictions, demonstrating that the mutated gene led to a 20% reduction in the activity level of the CARS protein.
Further analyses, including bioinformatics predictions and molecular analyses, strongly indicated that the mutation was the genetic cause of the observed neurological condition.
“These results identify a novel pathogenesis (disease-causing mechanisms) of parkinsonian-spinocerebellar ataxia and provide insights into its genetic architecture,” the researchers wrote.
