Associations between Neurological Diseases and Mutations in the Human Glycyl-tRNA Synthetase

Vinogradova, E. S.; Nikonov, Oleg; Nikonova, E. Yu.

doi:10.1134/s0006297921140029

Cited by 5 publications

(7 citation statements)

References 91 publications

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“…It catalyzes the attachment of glycine to its cognate tRNA. Mutations in the g e n e c o d i n g fo r h u m a n G l y R S ar e a s s o c ia te d t o neurodegenerative diseases including the distal spinal muscle atrophy type V and CMT disease (115). The impairment in the mitochondrial metabolism in neurons is one of the mechanisms through which mutations in GlyRS lead to neurological diseases (116).…”

Section: Glycl-trna Synthetasementioning

confidence: 99%

Aminoacyl-tRNA Synthetases: On Anti-Synthetase Syndrome and Beyond

et al. 2022

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Anti-synthetase syndrome (ASSD) is an autoimmune disease characterized by the presence of autoantibodies targeting one of several aminoacyl t-RNA synthetases (aaRSs) along with clinical features including interstitial lung disease, myositis, Raynaud’s phenomenon, arthritis, mechanic’s hands, and fever. The family of aaRSs consists of highly conserved cytoplasmic and mitochondrial enzymes, one for each amino acid, which are essential for the RNA translation machinery and protein synthesis. Along with their main functions, aaRSs are involved in the development of immune responses, regulation of transcription, and gene-specific silencing of translation. During the last decade, these proteins have been associated with cancer, neurological disorders, infectious responses, and autoimmune diseases including ASSD. To date, several aaRSs have been described to be possible autoantigens in different diseases. The most commonly described are histidyl (HisRS), threonyl (ThrRS), alanyl (AlaRS), glycyl (GlyRS), isoleucyl (IleRS), asparaginyl (AsnRS), phenylalanyl (PheRS), tyrosyl (TyrRS), lysyl (LysRS), glutaminyl (GlnRS), tryptophanyl (TrpRS), and seryl (SerRS) tRNA synthetases. Autoantibodies against the first eight autoantigens listed above have been associated with ASSD while the rest have been associated with other diseases. This review will address what is known about the function of the aaRSs with a focus on their autoantigenic properties. We will also describe the anti-aaRSs autoantibodies and their association to specific clinical manifestations, and discuss their potential contribution to the pathogenesis of ASSD.

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Section: Glycl-trna Synthetasementioning

confidence: 99%

Aminoacyl-tRNA Synthetases: On Anti-Synthetase Syndrome and Beyond

et al. 2022

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“…GARS1 encodes Glycyl-tRNA synthetase, a dually (cytoplasmic and mitochondrial) localized enzyme of the aminoacyl-tRNA synthetase (aaRS) family [ 38 , 39 ]. Defects in this enzyme’s activity result in the reduction of aminoacylation activity, changes in axon location, and alterations in the neuropilin 1 pathway [ 38 ] and lead to a CMT2 or dHMN type V phenotype, mainly involving the upper extremities at distal sites [ 16 ] ( Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

Rare among Rare: Phenotypes of Uncommon CMT Genotypes

et al. 2021

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(1) Background: Charcot–Marie–Tooth disease (CMT) is the most frequent form of inherited chronic motor and sensory polyneuropathy. Over 100 CMT causative genes have been identified. Previous reports found PMP22, GJB1, MPZ, and MFN2 as the most frequently involved genes. Other genes, such as BSCL2, MORC2, HINT1, LITAF, GARS, and autosomal dominant GDAP1 are responsible for only a minority of CMT cases. (2) Methods: we present here our records of CMT patients harboring a mutation in one of these rare genes (BSCL2, MORC2, HINT1, LITAF, GARS, autosomal dominant GDAP1). We studied 17 patients from 8 unrelated families. All subjects underwent neurologic evaluation and genetic testing by next-generation sequencing on an Ion Torrent PGM (Thermo Fischer) with a 44-gene custom panel. (3) Results: the following variants were found: BSCL2 c.263A > G p.Asn88Ser (eight subjects), MORC2 c.1503A > T p.Gln501His (one subject), HINT1 c.110G > C p.Arg37Pro (one subject), LITAF c.404C > G p.Pro135Arg (two subjects), GARS c.1660G > A p.Asp554Asn (three subjects), GDAP1 c.374G > A p.Arg125Gln (two subjects). (4) Expanding the spectrum of CMT phenotypes is of high relevance, especially for less common variants that have a higher risk of remaining undiagnosed. The necessity of reaching a genetic definition for most patients is great, potentially making them eligible for future experimentations.

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“…The human NARS2 protein is composed of 477 amino acids, which contains an-binding domain (ABD) and a catalytic domain. It exerts biological activity as a homodimer ( Vinogradova et al, 2021 ). Wild-type Leu62 is located in a pocket, surrounded by a hydrophobic group in the deep part of the protein, and forms hydrophobic bonds with surrounding residues.…”

Section: Resultsmentioning

confidence: 99%

“…Asparaginyl tRNA synthetase (NARS) is a subtype of class II aaRSs, similar to most aaRSs. It includes the cytoplasmic type NARS1 and the mitochondrial type NARS2 ( Vinogradova et al, 2021 ), both of which are associated with human neurodegenerative diseases. However, cytoplasmic and mitochondrial differences in protein localization and catalytic function can cause other diseases as well.…”

Section: Introductionmentioning

confidence: 99%

Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations

Fang

et al. 2022

Front. Neurosci.

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Biallelic NARS2 mutations can cause various neurodegenerative diseases, leading to growth retardation, intractable epilepsy, and hearing loss in early infancy and further progressing to spastic paraplegia, neurodegeneration, and even death. NARS2 mutations are associated with mitochondrial dysfunction and cause combined oxidative phosphorylation deficiency 24 (COXPD24). Relatively few cases have been reported worldwide; therefore, the pathogenesis of COXPD24 is poorly understood. We studied two unrelated patients with COXPD24 with similar phenotypes who presented with intractable refractory epilepsia partialis continua, hearing loss, and growth retardation. One patient died from epilepsy. Three novel NARS2 variants (case 1: c.185T > C and c.251 + 2T > G; case 2: c.185T > C and c.509T > G) were detected with whole-exome sequencing. c.251 + 2T > G is located at the donor splicing site in the non-coding sequence of the gene. The minigene experiment further verified that c.251 + 2T > G caused variable splicing abnormalities and produced truncated proteins. Molecular dynamics studies showed that c.185T > C and c.509T > G reduced the binding free energy of the NARS2 protein dimer. The literature review revealed fewer than 30 NARS2 variants. These findings improved our understanding of the disease phenotype and the variation spectrum and revealed the potential pathogenic mechanism of non-coding sequence mutations in COXPD24.

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Associations between Neurological Diseases and Mutations in the Human Glycyl-tRNA Synthetase

Cited by 5 publications

References 91 publications

Aminoacyl-tRNA Synthetases: On Anti-Synthetase Syndrome and Beyond

Aminoacyl-tRNA Synthetases: On Anti-Synthetase Syndrome and Beyond

Rare among Rare: Phenotypes of Uncommon CMT Genotypes

Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations

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