Two siblings with homozygous pathogenic splice-site variant in mitochondrial asparaginyl-tRNA synthetase (NARS2).
A homozygous missense mutation (c.822G>C) was found in the gene encoding the mitochondrial asparaginyl-tRNA synthetase (NARS2) in two siblings born to consanguineous parents. These siblings presented with different phenotypes: one had mild intellectual disability and epilepsy in childhood, whereas the other had severe myopathy. Biochemical analysis of the oxidative phosphorylation (OXPHOS) complexes in both siblings revealed a combined complex I and IV deficiency in skeletal muscle. In-gel activity staining after blue native-polyacrylamide gel electrophoresis confirmed the decreased activity of complex I and IV, and, in addition, showed the presence of complex V subcomplexes. Considering the consanguineous descent, homozygosity mapping and whole-exome sequencing were combined revealing the presence of one single missense mutation in the shared homozygous region. The c.822G>C variant affects the 3' splice site of exon 7, leading to skipping of the whole exon 7 and a part of exon 8 in the NARS2 mRNA. In EBV-transformed lymphoblasts, a specific decrease in the amount of charged mt-tRNA(Asn) was demonstrated as compared with controls. This confirmed the pathogenic nature of the variant. To conclude, the reported variant in NARS2 results in a combined OXPHOS complex deficiency involving complex I and IV, making NARS2 a new member of disease-associated aaRS2.
Department of Pediatric Neurology and Metabolism, Ghent University Hospital, Belgium.
Arnaud V
AV
Vanlander
Björn
B
Menten
Joél
J
Smet
Linda
L
De Meirleir
Tom
T
Sante
Boel
B
De Paepe
Sara
S
Seneca
Sarah F
SF
Pearce
Christopher A
CA
Powell
Sarah
S
Vergult
Alex
A
Michotte
Elien
E
De Latter
Lies
L
Vantomme
Michal
M
Minczuk
Rudy
R
Van Coster
D000328:Adult; D001226:Aspartate-tRNA Ligase / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002478:Cells, Cultured; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D006720:Homozygote; D006801:Humans; D008297:Male; D009135:Muscular Diseases / Q000235:genetics; D020125:Mutation, Missense; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D022821:RNA Splice Sites
D020033:Protein Isoforms; D022821:RNA Splice Sites; D001226:Aspartate-tRNA Ligase; C000601756:NARS2 protein, human
NARS2; combined oxidative phosphorylation deficiency; mitochondria; mitochondrial aminoacyl-tRNA synthetase