Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.
Jennifer FriedmanDesiree E SmithMahmoud Y IssaValentina StanleyRengang WangMarisa I MendesMeredith S WrightKristen WigbyAmber HildrethJohn R CrawfordAlanna E KoehlerShimul ChowdhuryShareef NahasLiting ZhaiZhiwen XuWing-Sze LoKiely N JamesDamir MusaevAndrea AccogliKether GuerreroLuan T TranTarek E I OmarTawfeg Ben-OmranDavid DimmockStephen F KingsmoreGajja S SalomonsMaha S ZakiGeneviève BernardJoseph G GleesonPublished in: Nature communications (2019)
Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.
Keyphrases
- early onset
- intellectual disability
- multiple sclerosis
- late onset
- amino acid
- genome wide
- copy number
- end stage renal disease
- white matter
- autism spectrum disorder
- chronic kidney disease
- genome wide identification
- endothelial cells
- induced apoptosis
- binding protein
- newly diagnosed
- zika virus
- transcription factor
- gene expression
- nitric oxide
- peritoneal dialysis
- cell death
- endoplasmic reticulum stress
- genome wide analysis
- clinical evaluation
- heat shock
- high density
- patient reported outcomes