Gene mutation linked to movement disorder, Parkinson’s symptoms
Inherited CARS mutation tied to difficulty walking, parkinsonism
Scientists have discovered a link between a mutation in the CARS gene and late-onset neurological disorders with symptoms, such as movement disorder, similar to those seen in Parkinson’s disease patients.
The mutation, known as CARS E795V, was identified as the cause of a neurological condition affecting nine people from four related families. This condition is characterized by mobility problems and signs of neurodegeneration. The mutation is inherited in an autosomal dominant manner, meaning that having the mutation in just one copy of the gene is enough to cause the condition.
“The research underscores the importance of genetic analysis in identifying the root causes of complex diseases and sets the stage 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, “A Cysteinyl‑tRNA Synthetase Mutation Causes Novel Autosomal‑Dominant Inheritance of a Parkinsonism/Spinocerebellar‑Ataxia Complex,” was published in Neuroscience Bulletin.
Nine patients, ranging in age from 42 to 62, from four different families exhibited characteristics like 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 conditions including Parkinson’s disease and others causing symptoms like tremors, muscle rigidity and slow movements.
Disease progression linked to core symptoms
Eight patients also showed pyramidal signs, or neurological symptoms that affect the muscles under voluntary control, leading to abnormal muscle tightness after contraction, muscle weakness, and over-responsive bodily reflexes.
Disease progression was found to be correlated with the severity of these core symptoms. Patients who had been dealing with the condition for more than eight years experienced a worsening of their symptoms, with all patients requiring wheelchairs after eight years.
Symptoms that only affected some of the patients included peripheral neuropathy (damage of the nerves outside the brain and spinal cord), cognitive impairment, erectile dysfunction, facial grimacing (the involuntary distortion of facial expressions), and stridor, a wheezing sound that occurs during breathing due to the partial obstruction of the upper airway.
Four of the nine affected individuals underwent brain MRI scans, which identified several degrees of neurodegeneration in brain regions including the substantia nigra, a key brain region affected in Parkinson’s disease.
Imaging analysis revealed a resemblance to the features seen in multiple system atrophy, an atypical form of parkinsonism. These included the accumulation of iron in certain brain areas and a decline in regional cerebral blood flow.
To uncover the cause of the disease, researchers performed a genetic screening which detected the E795V mutation in the CARS gene in all nine affected patients, but not in unaffected family members. No known disease-causing mutations linked to spinocerebellar ataxias were found. Similar to parkinsonism, this group of inherited neurological disorders causes progressive loss of muscle control, coordination, and balance.
The CARS gene is responsible for producing the cysteinyl-tRNA synthetase (CARS) protein, which plays a crucial role in regulating the incorporation of amino acids, the fundamental components of proteins, during the processes of cell growth and differentiation.
A mutation in this gene is thought to lead to structural alterations in the CARS protein, potentially affecting its function. Researchers validated these predictions, demonstrating that the mutated gene led to a 20% reduction in the activity level of the CARS protein.
Further analysis, including bioinformatics predictions and molecular assays, strongly indicated the mutation was the genetic cause of the observed neurological condition.
“These findings identify novel pathogenesis [disease-causing mechanisms] of Parkinsonism-spinocerebellar ataxia and provide insights into its genetic architecture,” the researchers wrote.
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