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Two siblings with homozygous pathogenic splice-site variant in mitochondrial asparaginyl-tRNA synthetase (NARS2)

(2015) HUMAN MUTATION. 36(2). p.222-231
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Abstract
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.
Keywords
C-OXIDASE DEFICIENCY, combined oxidative phosphorylation deficiency, RESPIRATORY-CHAIN, PONTOCEREBELLAR HYPOPLASIA, PERRAULT SYNDROME, LACTIC-ACIDOSIS, LEIGH-SYNDROME, HEARING-LOSS, BRAIN-STEM, COMPLEX-I, MUTATIONS, mitochondrial aminoacyl-tRNA synthetase, mitochondria, NARS2

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Citation

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MLA
Vanlander, Arnaud et al. “Two Siblings with Homozygous Pathogenic Splice-site Variant in Mitochondrial asparaginyl-tRNA Synthetase (NARS2).” HUMAN MUTATION 36.2 (2015): 222–231. Print.
APA
Vanlander, A., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., et al. (2015). Two siblings with homozygous pathogenic splice-site variant in mitochondrial asparaginyl-tRNA synthetase (NARS2). HUMAN MUTATION, 36(2), 222–231.
Chicago author-date
Vanlander, Arnaud, Björn Menten, Joél Smet, Linda De Meirleir, Tom Sante, Boel De Paepe, Sara Seneca, et al. 2015. “Two Siblings with Homozygous Pathogenic Splice-site Variant in Mitochondrial asparaginyl-tRNA Synthetase (NARS2).” Human Mutation 36 (2): 222–231.
Chicago author-date (all authors)
Vanlander, Arnaud, Björn Menten, Joél Smet, Linda De Meirleir, Tom Sante, Boel De Paepe, Sara Seneca, Sarah F Pearce, Christopher A Powell, Sarah Vergult, Alex Michotte, Elien De Latter, Lies Vantomme, Michal Minczuk, and Rudy Van Coster. 2015. “Two Siblings with Homozygous Pathogenic Splice-site Variant in Mitochondrial asparaginyl-tRNA Synthetase (NARS2).” Human Mutation 36 (2): 222–231.
Vancouver
1.
Vanlander A, Menten B, Smet J, De Meirleir L, Sante T, De Paepe B, et al. Two siblings with homozygous pathogenic splice-site variant in mitochondrial asparaginyl-tRNA synthetase (NARS2). HUMAN MUTATION. 2015;36(2):222–31.
IEEE
[1]
A. Vanlander et al., “Two siblings with homozygous pathogenic splice-site variant in mitochondrial asparaginyl-tRNA synthetase (NARS2),” HUMAN MUTATION, vol. 36, no. 2, pp. 222–231, 2015.
@article{5918773,
  abstract     = {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.},
  author       = {Vanlander, Arnaud and Menten, Björn and Smet, Joél and De Meirleir, Linda and Sante, Tom and De Paepe, Boel and Seneca, Sara and Pearce, Sarah F and Powell, Christopher A and Vergult, Sarah and Michotte, Alex and De Latter, Elien and Vantomme, Lies and Minczuk, Michal and Van Coster, Rudy},
  issn         = {1059-7794},
  journal      = {HUMAN MUTATION},
  keywords     = {C-OXIDASE DEFICIENCY,combined oxidative phosphorylation deficiency,RESPIRATORY-CHAIN,PONTOCEREBELLAR HYPOPLASIA,PERRAULT SYNDROME,LACTIC-ACIDOSIS,LEIGH-SYNDROME,HEARING-LOSS,BRAIN-STEM,COMPLEX-I,MUTATIONS,mitochondrial aminoacyl-tRNA synthetase,mitochondria,NARS2},
  language     = {eng},
  number       = {2},
  pages        = {222--231},
  title        = {Two siblings with homozygous pathogenic splice-site variant in mitochondrial asparaginyl-tRNA synthetase (NARS2)},
  url          = {http://dx.doi.org/10.1002/humu.22728},
  volume       = {36},
  year         = {2015},
}

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