Mutations in the mitochondrial tryptophanyl‐tRNA synthetase cause growth retardation and progressive leukoencephalopathy

Abstract

Background Mutations in mitochondrial aminoacyl tRNA synthetases form a subgroup of mitochondrial disorders often only perturbing brain function by affecting mitochondrial translation. Here we report two siblings with mitochondrial disease, due to compound heterozygous mutations in the mitochondrial tryptophanyl‐tRNA synthetase (WARS2) gene, presenting with severe neurological symptoms but normal mitochondrial function in skeletal muscle biopsies and cultured skin fibroblasts. Methods Whole exome sequencing on genomic DNA samples from both subjects and their parents identified two compound heterozygous variants c.833T>G (p.Val278Gly) and c.938A>T (p.Lys313Met) in the WARS2 gene as potential disease‐causing variants. We generated patient‐derived neuroepithelial stem cells and modeled the disease in yeast and Drosophila melanogaster to confirm pathogenicity. Results Biochemical analysis of patient‐derived neuroepithelial stem cells revealed a mild combined complex I and IV defect, while modeling the disease in yeast demonstrated that the reported aminoacylation defect severely affects respiration and viability. Furthermore, silencing of wild type WARS2 in Drosophila melanogaster showed that a partial defect in aminoacylation is enough to cause lethality. Conclusions Our results establish the identified WARS2 variants as disease‐causing and highlight the benefit of including human neuronal models, when investigating mutations specifically affecting the nervous system.

WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia

“…Similar to several of the previously described cases, this subject had a neonatal onset of symptoms and delay in developmental milestones, dominated by speech problems, ataxia, tremor, and paroxysmal exercise-induced leg weakness. While seizures were reported in previous cases of WARS2-related diseases [4,7,10], clinical seizures were not reported in relation to the pathological EEG findings in subject P6.…”

“…It is present in the gnomAD database in 922 heterozygous carriers and in six subjects in a homozygous state. This variant has been defined as pathogenic in several previous reports [3,4,6,9] and was shown to impact the correct localization of WARS2 protein in cells [5] and to variably affect the OXPHOS system [7]. Cumulative evidence therefore strongly suggests that p.(Trp13Gly) is a hypomorphic allele, which is disease-causing only when present in trans with loss-of-function alleles; due to this nature, the p.(Trp13Gly) variant often presents with milder disease phenotypes and later disease onset, as shown in several of our subjects.…”

“…A total of 19 mt-ARSs have been described; they all have been linked to human mitochondrial diseases with a broad range of clinical manifestations [2]. Recently, biallelic pathogenic variants in WARS2 (OMIM *604733) encoding the tryptophanyl mt-ARSs (mtTrpRS) have been reported in 16 individuals with neonatal or infantile-onset disease presenting with phenotypes ranging from intellectual disability [3], to infantile parkinsonism [4][5][6], leukoencephalopathy [7,8], complex hyperkinetic disorder [9], and neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (NEMMLAS) [10].…”

Epigenetic Alterations in Cryopreserved Human Spermatozoa: Suspected Potential Functional Defects

“…Alanyl-tRNA synthetase 2, with a mitochondrial (AARS2) mutation, has been reported in primary ovarian insufficiency, which can lead to abnormal aminoacylation of tRNA, affecting the process of mitochondrial translation and eventually leading to the occurrence of ovarian leukodystrophy syndrome [47]. Mutations in histidyl-tRNA synthetase 2, mitochondrial (HARS2), and leucyl-tRNA synthetase 2, mitochondrial (LARS2), are frequently associated with Perrault syndrome, which often leads to neuropathic hearing impairment and ovarian dysfunction in women [48,49]. However, there are no reports on mitochondrial tRNA aminoacylation affecting the male reproductive system.…”

A relatively common hypomorphic variant in WARS2 causes monogenic disease

“…Brain MRI showed thin corpus callosum, mildly reduced cerebral and cerebellar volume, and at age 6 years a transient juxtaventricular white matter hyperintensity. The same genotype had previously been described in two Swedish siblings with a similar disease phenotype [2], but families were not aware of any relatedness. One additional female patient with the recurrent p.(Trp13Gly) variant, in compound heterozygosity with the probably pathogenic c.487C>T p. (Leu163Phe) variant that is rare in gnomAD (0.0016%), had been reported from Portugal; the patient had mental retardation, tremor and dystonia that manifested at 2 years of age and progressed slowly [3].…”