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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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Chicago
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.
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.
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.
MLA
VANLANDER, ARNAUD, Björn Menten, Joél Smet, et al. “Two Siblings with Homozygous Pathogenic Splice-site Variant in Mitochondrial asparaginyl-tRNA Synthetase (NARS2).” HUMAN MUTATION 36.2 (2015): 222–231. Print.
@article{5918773,
  abstract     = {A homozygous missense mutation (c.822G{\textrangle}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{\textrangle}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, Bj{\"o}rn and Smet, Jo{\'e}l 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},
  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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