A Newly Identified Missense Mutation in<i>FARS2</i>Causes Autosomal-Recessive Spastic Paraplegia

Yang, Ying; Liu, Wei; Fang, Zhipeng; Shi, Juan; Che, Fengyu; He, Chun‐Xia; Yao, Libo; Wang, En‐Duo; Wu, Yuanming

doi:10.1002/humu.22930

Cited by 50 publications

(32 citation statements)

References 24 publications

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“…Our subject possessed novel compound heterozygous mutations in FARS2 (Q216X and P136H) resulting in a pure spastic paraplegia syndrome that was also associated with bilateral signal abnormalities of the dentate nuclei. His phenotype was similar to a previously reported consanguineous Chinese family with pure spastic paraplegia due to homozygous mutations within the catalytic domain of mtPheRS (D142Y), although their neuroimaging was normal . To date, these subjects represent the mildest cases of FARS2 ‐related disease.…”

Section: Discussionsupporting

confidence: 83%

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FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei

Sahai

Steiner

et al. 2018

Ann Clin Transl Neurol

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Mutations in FARS2, the gene encoding the mitochondrial phenylalanine‐tRNA synthetase (mtPheRS), have been linked to a range of phenotypes including epileptic encephalopathy, developmental delay, and motor dysfunction. We report a 9‐year‐old boy with novel compound heterozygous variants of FARS2, presenting with a pure spastic paraplegia syndrome associated with bilateral signal abnormalities in the dentate nuclei. Exome sequencing identified a paternal nonsense variant (Q216X) lacking the catalytic core and anticodon‐binding regions, and a maternal missense variant (P136H) possessing partial enzymatic activity. This case confirms and expands the phenotype related to FARS2 mutations with regards to clinical presentation and neuroimaging findings.

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Section: Discussionsupporting

confidence: 83%

“…More moderate phenotypes consisting of cognitive disability, motor delays, and epilepsy have also been reported . In its mildest form, FARS2 presented with a pure spastic paraplegia syndrome in a consanguineous Chinese family with homozygous mutations (spastic paraplegia type 77; SPG77 MIM#617046) …”

Section: Introductionmentioning

confidence: 99%

FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei

Sahai

Steiner

et al. 2018

Ann Clin Transl Neurol

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“…We also coded PavCA index score as a 233 binary trait using various thresholds to define cases (goal-trackers) and controls (sign-trackers); 234 this approach identified two genome-wide significant associations. The first locus was unique to Fars2 (Page 68 in S1 File; Fig 4B), a mitochondrial phenylalanyl-tRNA synthetase involved in 240 oxidative phosphorylation and neuronal functioning [31][32][33]. We then expanded our search to the average of days 4 and 5 for each of the 10 remaining 252 metrics individually.…”

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confidence: 99%

“…This locus was identified for multiple 343 metrics on days 4 and 5, as well as in the univariate analysis of the first PC from PCA on the 344 comprehensive set of all 55 metrics. All genome-wide significant SNPs were located in an intron 345 of Fars2 (Fig3B), which is highly expressed in the Purkinje cells of the cerebellum [31] but has 346 no previously known ties to behavior. Another promising locus for magazine entries and latency 347 to magazine entry during CS presentation was on chromosome 1.…”

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confidence: 99%

Genetic characterization of outbred Sprague Dawley rats and utility for genome-wide association studies

Gileta

Fitzpatrick

Chitre

et al. 2018

Preprint

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30Sprague Dawley (SD) rats are one of the most commonly used outbred rat strains. Despite 31 this, the genetic characteristics of SD are poorly understood. We collected behavioral data from 32 4,625 SD rats acquired predominantly from two commercial vendors, Charles River Laboratories 33 and Harlan Sprague Dawley Inc. Using double-digest genotyping-by-sequencing (ddGBS), we 34 obtained dense, high-quality genotypes at 234,887 SNPs across 4,061 rats. This genetic data 35 allowed us to characterize the variation present in Charles River vs. Harlan SD rats. We found that 36 the two populations are highly diverged (FST > 0.4). We also used these data to perform a genome-37 wide association study (GWAS) of Pavlovian conditioned approach (PavCA), which assesses the 38 propensity for rats to attribute motivational value to discrete, reward-associated cues. Due to the 39 genetic divergence between rats from Charles River and Harlan, we performed two separate 40 GWAS by fitting a linear mixed model that accounted for within vendor population structure and 41 using meta-analysis to jointly analyze the two studies. We identified 18 independent loci that were 42 significantly associated with one or more metrics used to describe PavCA; we also identified 3 43 loci that were body weight, which was only measured in a subset of the rats. The genetic 44 characterization of SD rats is a valuable resource for the rat community that can be used to inform 45 future study design. 46 AuthorSummary 47 Outbred Sprague Dawley rats are among the most commonly used rats for neuroscience, 48 physiology and pharmacological research. SD rats are sold by several commercial vendors, 49 including Charles River Laboratories and Harlan Sprague Dawley Inc. (now Envigo). Despite their 50wide spread use, little is known about the genetic diversity of SD. We genotyped more than 4,000 51 2 SD rats, which we used to characterize genetic differences between SD rats from Charles River 52 Laboratories and Harlan. Our analysis revealed that the two SD colonies are highly divergent. We 53 also performed a genome-wide association study (GWAS) for Pavlovian conditioned approach 54 (PavCA), which assesses the propensity for rats to attribute motivational value to discrete, reward-55 associated cues. Our results demonstrate that, despite sharing an identical name, SD rats are 56 obtained from different vendors are genetically very different. We conclude that results obtained 57 using SD rats should not be presented without also carefully noting the vendor. 58 Introduction 59Rats are among the most commonly used organisms for experimental psychology and 60 biomedical research. Whereas research using mice makes extensive use of inbred strains, in rats, 61 it is more common to use commercially available outbred populations. Among the commercially 62 available outbred rat populations, the Sprague Dawley strain (SD) is one of the most widely used. 63SD rats are distributed by several vendors. Each vendor has multiple breeding locations, and each 64 breeding locatio...

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“…To date at least 21 pathogenic variants have been reported for HsmitPheRS that were found to be associated with disease conditions with moderate to severe symptoms. The clinical phenotypic expression of the pathogenic variants of the FARS2 gene show pleiotropic effects, from spastic paraplegia to infantile Alpers encephalopathy (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). The effects of some of these mutations on enzyme function have been investigated.…”

Section: Introductionmentioning

confidence: 99%

Biophysical characterization Of Alpers encephalopathy associated mutants of human mitochondrial phenylalanyl‐tRNA synthetase

2019

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Mutations in nucleus‐encoded mitochondrial aminoacyl‐tRNA synthetases (mitaaRSs) lead to defects in mitochondrial translation affecting the expression and function of 13 subunits of the respiratory chain complex leading to diverse pathological conditions. Mutations in the FARS2 gene encoding human mitochondrial phenylalanyl‐tRNA synthetase (HsmitPheRS) have been found to be associated with two different clinical representations, infantile Alpers encephalopathy and spastic paraplegia. Here we have studied three pathogenic mutants (Tyr144Cys, Ile329Thr, and Asp391Val) associated with Alpers encephalopathy to understand how these variants affect the biophysical properties of the enzyme. These mutants have already been reported to have reduced aminoacylation activity. Our study established that the mutants are significantly more thermolabile compared to the wild‐type enzyme with reduced solubility in vitro. The presence of aggregation‐prone insoluble HsmitPheRS variants could have a detrimental impact on organellar translation, and potentially impact normal mitochondrial function. © 2019 IUBMB Life, 71(8): 1141–1149, 2019 © 2019 IUBMB Life, 71(8):1141–1149, 2019

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A Newly Identified Missense Mutation inFARS2Causes Autosomal-Recessive Spastic Paraplegia

Cited by 50 publications

References 24 publications

FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei

FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei

Genetic characterization of outbred Sprague Dawley rats and utility for genome-wide association studies

Biophysical characterization Of Alpers encephalopathy associated mutants of human mitochondrial phenylalanyl‐tRNA synthetase

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