Yi Zhang1, Xiangyue Zhao1, Yufei Xu1, Lina Chen1, Niu Li1, Ruen Yao1, Xiumin Wang2, Jian Wang1, Tingting Yu1. 1. Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 2. Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Abstract
Background: NARS2 catalyzes the attachment of asparagine amino acids to mitochondrial tRNAAsn and is critical for efficient mitochondrial protein synthesis. Biallelic variants in NARS2 are associated with combined oxidative phosphorylation deficiency 24 (COXPD24) and autosomal recessive deafness-94. Methods: Patient information was obtained after recruitment. Genetic tests were performed using whole exome sequencing (WES) and Sanger sequencing. Structure prediction was based on the RaptorX and SWISS-MODEL platforms. The mRNA analysis of paternal variant was performed. Expression levels and dimerization of wild-type (WT) and mutant NARS2 were detected in human embryonic kidney (HEK) 293T cells. Mitochondrial localization of NARS2 variants was determined using immunofluorescence staining. Results: The patient presented early onset generalized epilepsy, myoclonic seizures, severe bilateral hearing impairment and affected liver and heart. WES identified two compound heterozygous variants in NARS2: c.1141A>G/p.Asn381Asp and c.1290G>C/p.Trp430Cys. In silico analysis predicted that both variants would cause significant and pathogenic changes in secondary structure. NARS2 c.1290G>C is a variant at the first nucleotide of an exon, a location thought to affect mRNA splicing. Although transcriptional experiments did not identify aberrant splicing, we observed a lower proportion of transcripts from the NARS2 c.1290G>C variant. An in vitro experiment showed that both variants impaired NARS2 expression, while mitochondrial localization and dimerization remained unaffected. Conclusions: The patient was diagnosed with COXPD24 caused by novel NARS2 variations. The cardiac dysfunction is identified for the first time. In vitro study revealed impairment of variants on NARS2 expression. These data enrich our knowledge regarding the phenotypic and genotypic spectra of NARS2. 2022 Translational Pediatrics. All rights reserved.
Background: NARS2 catalyzes the attachment of asparagine amino acids to mitochondrial tRNAAsn and is critical for efficient mitochondrial protein synthesis. Biallelic variants in NARS2 are associated with combined oxidative phosphorylation deficiency 24 (COXPD24) and autosomal recessive deafness-94. Methods: Patient information was obtained after recruitment. Genetic tests were performed using whole exome sequencing (WES) and Sanger sequencing. Structure prediction was based on the RaptorX and SWISS-MODEL platforms. The mRNA analysis of paternal variant was performed. Expression levels and dimerization of wild-type (WT) and mutant NARS2 were detected in human embryonic kidney (HEK) 293T cells. Mitochondrial localization of NARS2 variants was determined using immunofluorescence staining. Results: The patient presented early onset generalized epilepsy, myoclonic seizures, severe bilateral hearing impairment and affected liver and heart. WES identified two compound heterozygous variants in NARS2: c.1141A>G/p.Asn381Asp and c.1290G>C/p.Trp430Cys. In silico analysis predicted that both variants would cause significant and pathogenic changes in secondary structure. NARS2 c.1290G>C is a variant at the first nucleotide of an exon, a location thought to affect mRNA splicing. Although transcriptional experiments did not identify aberrant splicing, we observed a lower proportion of transcripts from the NARS2 c.1290G>C variant. An in vitro experiment showed that both variants impaired NARS2 expression, while mitochondrial localization and dimerization remained unaffected. Conclusions: The patient was diagnosed with COXPD24 caused by novel NARS2 variations. The cardiac dysfunction is identified for the first time. In vitro study revealed impairment of variants on NARS2 expression. These data enrich our knowledge regarding the phenotypic and genotypic spectra of NARS2. 2022 Translational Pediatrics. All rights reserved.
Authors: K Štěrbová; M Vlčková; H Hansíková; V Sebroňová; L Sedláčková; P Pavlíček; Petra Laššuthová Journal: Neurogenetics Date: 2021-08-20 Impact factor: 2.660
Authors: Mariella Simon; Elodie M Richard; Xinjian Wang; Mohsin Shahzad; Vincent H Huang; Tanveer A Qaiser; Prasanth Potluri; Sarah E Mahl; Antonio Davila; Sabiha Nazli; Saege Hancock; Margret Yu; Jay Gargus; Richard Chang; Nada Al-Sheqaih; William G Newman; Jose Abdenur; Arnold Starr; Rashmi Hegde; Thomas Dorn; Anke Busch; Eddie Park; Jie Wu; Hagen Schwenzer; Adrian Flierl; Catherine Florentz; Marie Sissler; Shaheen N Khan; Ronghua Li; Min-Xin Guan; Thomas B Friedman; Doris K Wu; Vincent Procaccio; Sheikh Riazuddin; Douglas C Wallace; Zubair M Ahmed; Taosheng Huang; Saima Riazuddin Journal: PLoS Genet Date: 2015-03-25 Impact factor: 5.917