Mutations of Human NARS2, Encoding the Mitochondrial Asparaginyl-tRNA Synthetase, Cause Nonsyndromic Deafness and Leigh Syndrome

Abstract

Here we demonstrate association of variants in the mitochondrial asparaginyl-tRNA synthetase NARS2 with human hearing loss and Leigh syndrome. A homozygous missense mutation ([c.637G>T; p.Val213Phe]) is the underlying cause of nonsyndromic hearing loss (DFNB94) and compound heterozygous mutations ([c.969T>A; p.Tyr323*] + [c.1142A>G; p.Asn381Ser]) result in mitochondrial respiratory chain deficiency and Leigh syndrome, which is a neurodegenerative disease characterized by symmetric, bilateral lesions in the basal ganglia, thalamus, and brain stem. The severity of the genetic lesions and their effects on NARS2 protein structure cosegregate with the phenotype. A hypothetical truncated NARS2 protein, secondary to the Leigh syndrome mutation p.Tyr323* is not detectable and p.Asn381Ser further decreases NARS2 protein levels in patient fibroblasts. p.Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNAAsn in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome.

Biallelic variants inWARS2encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy

“…In these individual's fibroblasts, a defect on aminoacylation of tRNA Trp in fibroblast was detected, while no clear decrease in OXPHOS enzyme activity was observed. This tissue specificity has been reported previously for other mt‐aaRS genes, such as TARS2 (Diodato et al., ) and NARS2 (Simon et al., ), and could indicate that the residual mt‐aaRS activity and accompanying low levels of tRNA aminoacylation are still sufficient to generate normally functioning OXPHOS enzymes in a tissue‐specific manner.…”

“…Similar observations have been made for defects in other mt-aaRS related mitochondrial disorders Konovalova & Tyynismaa, 2013 and NARS2 (Simon et al, 2015),…”

The role of tRNA synthetases in neurological and neuromuscular disorders

“…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 .…”

Clinical, biochemical, and genetic features associated with VARS2 -related mitochondrial disease

“…Mitochondrial aminoacyl‐tRNA synthetases (mt‐aaRSs) are key enzymes in mitochondrial protein synthesis since they catalyze the specific attachment of amino acids to their cognate tRNAs. Recently, an increasing number of mitochondrial disorders have been associated with variants in mt‐aaRSs genes [Coughlin et al., ; Diodato et al., a,a; Konovalova & Tyynismaa, ; Simon et al., ]. However, for some mt‐aaRSs (i.e., VARS2, MIM# 615917), very few individual patients have been described and the associated phenotype is thus poorly defined.…”