Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities

Salvarinova, Ramona; Ye, Cynthia X.; Rossi, Andrea; Biancheri, Roberta; Roland, Elke H.; Pavlidis, Paul; Ross, Colin J.; Tarailo‐Graovac, Maja; Wasserman, Wyeth W.

doi:10.1007/s10048-014-0432-y

Cited by 14 publications

(15 citation statements)

References 7 publications

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“…Compound heterozygous mutations in human GlnRS were reported in multiple nonconsanguineous families to cause brain atrophy and disorders of the central nervous system ( 28 , 52 , 53 ). Of the four pathological mutations analyzed in this study, R403W and R515W inflict particularly harmful effects onto GlnRS.…”

Section: Discussionmentioning

confidence: 99%

“…reported that compound heterozygous mutations, Y57H and K496*, cause early-onset epileptic encephalopathy ( 52 ), while in the other, Salvarinova et al . reported that R463* and Q742H mutations, which are encoded on separate alleles, elicit isolated supratentorial brain abnormalities ( 53 ). The latter phenotype is similar to the one described by Zhang et al .…”

Section: Discussionmentioning

confidence: 99%

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The crystal structure of human GlnRS provides basis for the development of neurological disorders

Ognjenović

Matthies

et al. 2016

Nucleic Acids Res

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Cytosolic glutaminyl-tRNA synthetase (GlnRS) is the singular enzyme responsible for translation of glutamine codons. Compound heterozygous mutations in GlnRS cause severe brain disorders by a poorly understood mechanism. Herein, we present crystal structures of the wild type and two pathological mutants of human GlnRS, which reveal, for the first time, the domain organization of the intact enzyme and the structure of the functionally important N-terminal domain (NTD). Pathological mutations mapping in the NTD alter the domain structure, and decrease catalytic activity and stability of GlnRS, whereas missense mutations in the catalytic domain induce misfolding of the enzyme. Our results suggest that the reduced catalytic efficiency and a propensity of GlnRS mutants to misfold trigger the disease development. This report broadens the spectrum of brain pathologies elicited by protein misfolding and provides a paradigm for understanding the role of mutations in aminoacyl-tRNA synthetases in neurological diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The crystal structure of human GlnRS provides basis for the development of neurological disorders

Ognjenović

Matthies

et al. 2016

Nucleic Acids Res

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“…Solid line indicates dominant mode of inheritance, dashed line indicates recessive mode of inheritance. References: AARS , DARS , HARS , IARS MARS , RARS , S ARS , W ARS , ARS , QARS , GARS , KARS , AARS 2 , CARS 2 , DARS 2 , EARS 2 , FARS 2 , HARS 2 , IARS 2 , LARS 2 , MARS 2 , NARS 2 , PARS 2 , RARS 2 , S ARS 2 , TARS 2 , VARS 2 , WARS 2 , YARS 2 .…”

Section: Mitochondrial Trna Synthetases (Ars2 Genes)mentioning

confidence: 99%

The role of tRNA synthetases in neurological and neuromuscular disorders

2018

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Aminoacyl‐tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNAs with their cognate amino acids, therefore essential for the first step in protein synthesis. Although the majority of protein synthesis happens in the cytosol, an additional translation apparatus is required to translate the 13 mitochondrial DNA‐encoded proteins important for oxidative phosphorylation. Most ARS genes in these cellular compartments are distinct, but two genes are common, encoding aminoacyl‐tRNA synthetases of glycine (GARS) and lysine (KARS) in both mitochondria and the cytosol. Mutations in the majority of the 37 nuclear‐encoded human ARS genes have been linked to a variety of recessive and dominant tissue‐specific disorders. Current data indicate that impaired enzyme function could explain the pathogenicity, however not all pathogenic ARSs mutations result in deficient catalytic function; thus, the consequences of mutations may arise from other molecular mechanisms. The peripheral nerves are frequently affected, as illustrated by the high number of mutations in cytosolic and bifunctional tRNA synthetases causing Charcot–Marie–Tooth disease (CMT). Here we provide insights on the pathomechanisms of CMT‐causing tRNA synthetases with specific focus on the two bifunctional tRNA synthetases (GARS, KARS).

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“…The affected patient was a compound heterozygous for R463 Ã and Q742H and exhibited progressive microcephaly with diffuse cerebral atrophy, severely deficient myelination, intractable seizures, and developmental arrest. 77 Besides PCH, mutations in QARS and RARS2 cause Early-Onset Epileptic Encephalopathy (EOEE), a group of damaging diseases characterized by early-onset seizures, developmental delay, and poor prognosis ( Table 1). In the first study, 2 siblings were compound heterozygous for Y57H and K496 Ã in QARS.…”

Section: Severe Early-onset Brain Disordersmentioning

confidence: 99%

Human aminoacyl-tRNA synthetases in diseases of the nervous system

Ognjenović

Simonović

2017

RNA Biology

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Aminoacyl-tRNA synthetases (AaRSs) are ubiquitously expressed enzymes that ensure accurate translation of the genetic information into functional proteins. These enzymes also execute a variety of non-canonical functions that are significant for regulation of diverse cellular processes and that reside outside the realm of protein synthesis. Associations between faults in AaRS-mediated processes and human diseases have been long recognized. Most recent research findings strongly argue that 10 cytosolic and 14 mitochondrial AaRSs are implicated in some form of pathology of the human nervous system. The advent of modern whole-exome sequencing makes it all but certain that similar associations between the remaining 15 ARS genes and neurologic illnesses will be defined in future. It is not surprising that an intense scientific debate about the role of translational machinery, in general, and AaRSs, in particular, in the development and maintenance of the healthy human neural cell types and the brain is sparked. Herein, we summarize the current knowledge about causative links between mutations in human AaRSs and diseases of the nervous system and briefly discuss future directions.

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Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities

Cited by 14 publications

References 7 publications

The crystal structure of human GlnRS provides basis for the development of neurological disorders

The crystal structure of human GlnRS provides basis for the development of neurological disorders

The role of tRNA synthetases in neurological and neuromuscular disorders

Human aminoacyl-tRNA synthetases in diseases of the nervous system

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