Functional Analyses of Glycyl-tRNA Synthetase Mutations Suggest a Key Role for tRNA-Charging Enzymes in Peripheral Axons

Antonellis, Anthony; Lee-Lin, Shih Queen; Wasterlain, Amy S.; Leo, Paul; Quezado, Martha; Goldfarb, Lev G.; Myung, Kyungjae; Burgess, Shawn M.; Fischbeck, Kenneth H.; Green, Eric D.

doi:10.1523/jneurosci.1671-06.2006

Cited by 115 publications

(175 citation statements)

References 33 publications

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“…This may indicate that the level of GARS is more crucial during development than in adult mice; clearly the developmental profile of this enzyme warrants further investigation. We note that no difference in GARS protein levels was found between lymphoblastoid cell lines from a human GARS G240R/+ heterozygous patient and a wild-type individual (Antonellis et al, 2006); this is similar to our findings for adult Gars C201R/+ heterozygous mice compared with wild-type mice.…”

Section: Discussionsupporting

confidence: 91%

An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy

Achilli

Bros-Facer

Williams

et al. 2009

Disease Models &Amp; Mechanisms

167

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C201R, with a point mutation that leads to a non-conservative substitution within GARS. Heterozygous mice with a C3H genetic background have loss of grip strength, decreased motor flexibility and disruption of fine motor control; this relatively mild phenotype is more severe on a C57BL/6 background. Homozygous mutants have a highly deleterious set of features, including movement difficulties and death before weaning. Heterozygous animals have a reduction in axon diameter in peripheral nerves, slowing of nerve conduction and an alteration in the recovery cycle of myelinated axons, as well as innervation defects. An assessment of GARS levels showed increased protein in 15-day-old mice compared with controls; however, this increase was not observed in 3-month-old animals, indicating that GARS function may be more crucial in younger animals. We found that enzyme activity was not reduced detectably in heterozygotes at any age, but was diminished greatly in homozygous mice compared with controls; thus, homozygous animals may suffer from a partial loss of function. The Gars C201R mutation described here is a contribution to our understanding of the mechanism by which mutations in tRNA synthetases, which are fundamentally important, ubiquitously expressed enzymes, cause axonopathy in specific sets of neurons.

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Section: Discussionsupporting

confidence: 91%

An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy

Achilli

Bros-Facer

Williams

et al. 2009

Disease Models &Amp; Mechanisms

167

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“…All 13 proteins are subunits of the respiratory chain complexes (I-IV) and ATP synthase (complex V) (to be complemented by about 70 subunits of nuclear origin) and are thus directly linked to the energy metabolism. More and more pathologies linked to the mitochondrial translation machinery become discovered (Jacobs and Turnbull 2005), including aminoacyl-tRNA synthetases as major targets (Antonellis et al 2006;Scheper et al 2007). This is to say the central importance of tRNA genes to mitochondrial activity and the importance of understanding both their diversity and their uniqueness.…”

Section: Resultsmentioning

confidence: 99%

Mamit-tRNA, a database of mammalian mitochondrial tRNA primary and secondary structures

Pütz¹,

Dupuis²,

Sissler³

et al. 2007

RNA

143

144

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Mamit-tRNA (http://mamit-tRNA.u-strasbg.fr), a database for mammalian mitochondrial genomes, has been developed for deciphering structural features of mammalian mitochondrial tRNAs and as a helpful tool in the frame of human diseases linked to point mutations in mitochondrial tRNA genes. To accommodate the rapid growing availability of fully sequenced mammalian mitochondrial genomes, Mamit-tRNA has implemented a relational database, and all annotated tRNA genes have been curated and aligned manually. System administrative tools have been integrated to improve efficiency and to allow real-time update (from GenBank Database at NCBI) of available mammalian mitochondrial genomes. More than 3000 tRNA gene sequences from 150 organisms are classified into 22 families according to the amino acid specificity as defined by the anticodon triplets and organized according to phylogeny. Each sequence is displayed linearly with color codes indicating secondary structural domains and can be converted into a printable two-dimensional (2D) cloverleaf structure. Consensus and typical 2D structures can be extracted for any combination of primary sequences within a given tRNA specificity on the basis of phylogenetic relationships or on the basis of structural peculiarities. Mamit-tRNA further displays static individual 2D structures of human mitochondrial tRNA genes with location of polymorphisms and pathology-related point mutations. The site offers also a table allowing for an easy conversion of human mitochondrial genome nucleotide numbering into conventional tRNA numbering. The database is expected to facilitate exploration of structure/function relationships of mitochondrial tRNAs and to assist clinicians in the frame of pathology-related mutation assignments.

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“…The phenotypic spectrum of disorders associated with GARS mutations has been summarised in detail [6,9]. Recent functional analyses of several disease-associated GARS mutations suggested tRNA-charging deficits to play a role in disease pathogenesis [10]. In a number of families diagnosed as either dHMN-V or SS two heterozygous mutations (N88S, S90L) located in exon 3 in the Berardinelli-Seip congenital lipodystrophy gene (BSCL2) were identified [11].…”

Section: Introductionmentioning

confidence: 99%

Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome

Rohkamm

Reilly

Lochmüller

et al. 2007

Journal of the Neurological Sciences

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Objective-Distal hereditary motor neuropathy type V (dHMN-V) and Charcot-Marie-Tooth syndrome (CMT) type 2 presenting with predominant hand involvement, also known as CMT2D and Silver syndrome (SS) are rare phenotypically overlapping diseases which can be caused by mutations in the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) and in the glycyl-tRNA synthetase encoding (GARS) genes. Mutations in the heat-shock proteins HSPB1 and HSPB8 can cause related distal hereditary motor neuropathies (dHMN) and are considered candidates for dHMN-V, CMT2, and SS.Design-To define the frequency and distribution of mutations in the GARS, BSCL2, HSPB1 and HSPB8 genes we screened 33 unrelated sporadic and familial patients diagnosed as either dHMN-V, CMT2D or SS. Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsResults-Four patients diagnosed with dHMN-Vor SS carried known heterozygous BSCL2 mutations (N88S and S90L). In one dHMN-V patient we detected a putative GARS mutation (A57V). No mutations were detected in HSPB1 and HSPB8. The diagnostic yield gained in the series of 33 probands was 12% for BSCL2 mutations and 3% for GARS mutations. In the series of unclassified dHMN and complicated HSP cases no mutations were found.Conclusions-Our data confirm that most likely only two mutations (N88S, S90L) in exon 3 of BSCL2 may lead to dHMN-V or SS phenotypes. Mutations in GARS, HSPB1 and HSPB8. are not a common cause of dHMN-V, SS and CMT2D. We would therefore suggest that a genetic testing of dHMN-V and SS patients should begin with screening of exon 3 of the BSCL2 gene. Screening of the GARS gene is useful in patients with CMT2 with predominant hand involvement and dHMN-V. The rather low frequencies of BSCL2, GARS, HSPB1 and HSPB8 mutations in dHMN-V, CMT2D and SS patients strongly point to further genetic heterogeneity of these related disorders.

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Functional Analyses of Glycyl-tRNA Synthetase Mutations Suggest a Key Role for tRNA-Charging Enzymes in Peripheral Axons

Cited by 115 publications

References 33 publications

An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy

An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy

Mamit-tRNA, a database of mammalian mitochondrial tRNA primary and secondary structures

Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome

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