Novel CARS E795V Mutation Causing Inherited Parkinson's Disease | BGI Insight



According to Science Alert, neuroscientists from Johns Hopkins University have recently discovered a new treatment for Parkinson's disease using an FDA-approved cancer drug.  A recent study published in Neuroscience Bulletin reveals the genetic cause of Parkinson's disease. The study discovered that a mutation in the Cysteinyl-tRNA synthetase (CARS) gene (c.2384A>T; p.Glu795Val; E795V) is responsible, offering a new path for prevention and control of the disease. This research was conducted by a team led by Zhang Jianguo, including researcher Liu Hankui from BGI Genomics.

CARS Gene Mutation Led to Genetic Disorders

According to the National Institute of Health (NIH), the Cysteinyl-tRNA synthetase (CARS) gene controls the process of amino acid synthesis. Besides, this gene is involved in various biological processes, including cell growth, angiogenesis, migration, proliferation, and differentiation. When the gene cannot be coded normally, biological processes are disrupted, leading to the occurrence of diseases.

Autosomal dominant inheritance is one way a genetic trait or condition can be inherited. In this type of inheritance, the presence of a variant in just one allele (copy) of a specific gene is sufficient to cause the genetic condition, as NIH suggests. A single mutated gene copy from either parent can cause the condition when genetic disorders follow an autosomal-dominant inheritance pattern.

Same Genetic Sign

The study, using whole genome sequencing (WGS) and linkage analysis, found abnormal repeat expansion sites, pathogenic variants, and new rare mutations. Thirty members from this 90-member family have participated in this study. The CARS E795V mutation results in a novel autosomal-dominant inheritance of a neurological condition, affecting nine individuals from four families. These individuals, aged 42 to 62, exhibited symptoms such as difficulty walking, cerebellar ataxia, parkinsonism, and other neurodegenerative signs over 1 to 25 years.

The results of brain magnetic resonance imaging (MRI) scans showed signs of neurodegeneration. Whole-genome sequencing (WGS) indicated that all family members carrying a heterozygous CARS (E795V) mutation had the same clinical manifestations and neuropathological changes of parkinsonism and spinocerebellar ataxias (SCAs). Both the MRI and WGS results support the conclusion that the CARS E795V mutation highly affects the neurological condition of this family.

Different Neurodegenerative Symptoms

As the disease progressed, individuals affected for more than eight years began experiencing a range of neurodegenerative symptoms along with mobility issues. These varied across different families: one family faced peripheral neuropathy and vertical gaze dysfunction, another dealt with cognitive impairment, stridor, and cold hands, a third encountered erectile dysfunction, and two families observed facial grimacing.

Brain MRI scans of four affected individuals showed atrophy in the cerebellar cortex, vermis, and pons. Advanced imaging techniques highlighted characteristics similar to Multiple System Atrophy with Cerebellar features (MSA-C), including iron buildup in specific brain regions and reduced regional cerebral blood flow, which worsened over two years.


Fig.1 A. Four affected members (III-7, IV-5, IV-12, and IV-15) and three age-matched unaffected members (III-5, III-9, and IV-1) were used for whole-genome sequencing. All 30 members (except for IV-26 and V-24 with failure of Sanger sequencing) with available DNA are marked with (+) or without (–) the CARS mutation.

To uncover the genetic cause of this disease, researchers performed Whole-Genome Sequencing (WGS) on four affected individuals and three unaffected, age-matched individuals. This thorough analysis showed normal expansion levels at 11 repeat-expansion loci of Spinocerebellar Ataxias (SCAs) in all participants, and no known pathogenic mutations linked to SCAs were found.

Mutation Discovered

The WGS results revealed a common mutation: the E795V mutation was present in all nine affected individuals but absent in the seven unaffected individuals at or near the age of disease onset. The CARS mutation is extremely rare, not commonly found in the Chinese population databases such as the China Metabolic Analytics Project (ChinaMAP), the Han Chinese Genomes Database (PGG.Han), or the gnomAD v3 database.


Fig 2. Molecular dynamics experiment indicated a 20% decrease of mutant CARS activity (red), in the comparison of wild type (black) and a mutant CARS (c.2061) known to reduce activity (blue).

The rare CARS E795V mutation is predicted to have a harmful impact on gene function and cause structural changes in the protein. Laboratory tests confirmed that the mutant CARS had a 20% reduction in aminoacylation activity compared to the wild-type (Fig.2). These findings, supported by bioinformatics predictions, statistical evidence, and molecular assays, strongly indicate that this mutation is the genetic cause of the observed neurological condition.

The discovery of the CARS mutation in neurological conditions opens new paths for understanding and potentially treating this debilitating illness. This study demonstrates that previously known mutations are not responsible for the disease while confirming that the CARS E795V mutation is the leading cause of this neurological condition, closely related to Parkinson's disease. 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.

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