Novel phenotype and genotype spectrum of NARS2 and literature review of previous mutations

Vafaee-Shahi, Mohammad; Farhadi, Mohammad; Razmara, Ehsan; Morovvati, Saeid; Ghasemi, Saeide; Abedini, Seyedeh Sedigheh; Bagher, Zohreh; Alizadeh, Rafieh; Falah, Masoumeh

doi:10.1007/s11845-021-02736-7

Cited by 13 publications

(27 citation statements)

References 57 publications

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“…We searched 14 articles related to neural performance affected by NARS2 mutations ( Simon et al, 2015 ; Sofou et al, 2015 ; Vanlander et al, 2015 ; Mizuguchi et al, 2017 ; Souza et al, 2017 ; Seaver et al, 2018 ; Han et al, 2019 ; Lee et al, 2020 ; Štěrbová et al, 2021 ; Tanaka et al, 2022 ; Vafaee-Shahi et al, 2022 ; Yagasaki et al, 2022 ; Yang et al, 2022 ; Zhang et al, 2022 ). A total of 21 patients and 23 NARS2 mutations were reported in 16 families, most of which were missense mutations (91%, 21/23), followed by nonsense and frameshift mutations.…”

Section: Resultsmentioning

confidence: 99%

“…Most infants diagnosed with COXPD24 have sensorineural hearing loss in the early stage, followed by delayed neural development, intractable seizures, and hypotonia. MRI shows white matter lesions, mainly involving the frontal and parietal lobes and the deep white matter, and features of agenesis of the corpus callosum or diffuse brain atrophy ( Simon et al, 2015 ; Sofou et al, 2015 ; Vanlander et al, 2015 ; Mizuguchi et al, 2017 ; Souza et al, 2017 ; Seaver et al, 2018 ; Han et al, 2019 ; Lee et al, 2020 ; Štěrbová et al, 2021 ; Tanaka et al, 2022 ; Vafaee-Shahi et al, 2022 ; Yagasaki et al, 2022 ; Yang et al, 2022 ; Zhang et al, 2022 ). The characteristics of Leigh syndrome can be observed in some patients’ brain MRI or autopsy results, including symmetric long T2 abnormal signals in the brain stem or the putamen or atrophy of the corpus callosum with lamellar necrosis and vacuolization ( Simon et al, 2015 ; Tanaka et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

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Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations

Fang

et al. 2022

Front. Neurosci.

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Biallelic NARS2 mutations can cause various neurodegenerative diseases, leading to growth retardation, intractable epilepsy, and hearing loss in early infancy and further progressing to spastic paraplegia, neurodegeneration, and even death. NARS2 mutations are associated with mitochondrial dysfunction and cause combined oxidative phosphorylation deficiency 24 (COXPD24). Relatively few cases have been reported worldwide; therefore, the pathogenesis of COXPD24 is poorly understood. We studied two unrelated patients with COXPD24 with similar phenotypes who presented with intractable refractory epilepsia partialis continua, hearing loss, and growth retardation. One patient died from epilepsy. Three novel NARS2 variants (case 1: c.185T > C and c.251 + 2T > G; case 2: c.185T > C and c.509T > G) were detected with whole-exome sequencing. c.251 + 2T > G is located at the donor splicing site in the non-coding sequence of the gene. The minigene experiment further verified that c.251 + 2T > G caused variable splicing abnormalities and produced truncated proteins. Molecular dynamics studies showed that c.185T > C and c.509T > G reduced the binding free energy of the NARS2 protein dimer. The literature review revealed fewer than 30 NARS2 variants. These findings improved our understanding of the disease phenotype and the variation spectrum and revealed the potential pathogenic mechanism of non-coding sequence mutations in COXPD24.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations

Fang

et al. 2022

Front. Neurosci.

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“…Mutations in NARS2 are associated with combined oxidative phosphorylation deficiency 24 and autosomal recessive deafness 94. Seizures and hearing impairments were most common in the clinical findings of NARS2 patients 35 . A previous study reported a patient with novel NARS2 variants, causing infantile-onset severe epilepsy.…”

Section: Discussionmentioning

confidence: 96%

Use of dual genomic sequencing to screen mitochondrial diseases in pediatrics: a retrospective analysis

Peng

et al. 2023

Sci Rep

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Mitochondrial diseases (MDs) were a large group multisystem disorders, attributable in part to the dual genomic control. The advent of massively sequencing has improved diagnostic rates and speed, and was increasingly being used as a first-line diagnostic test. Paediatric patients (aged < 18 years) who underwent dual genomic sequencing were enrolled in this retrospective multicentre study. We evaluated the mitochondrial disease criteria (MDC) and molecular diagnostic yield of dual genomic sequencing. Causative variants were identified in 177 out of 503 (35.2%) patients using dual genomic sequencing. Forty-six patients (9.1%) had mitochondria-related variants, including 25 patients with nuclear DNA (nDNA) variants, 15 with mitochondrial DNA (mtDNA) variants, and six with dual genomic variants (MT-ND6 and POLG; MT-ND5 and RARS2; MT-TL1 and NARS2; MT-CO2 and NDUFS1; MT-CYB and SMARCA2; and CHRNA4 and MT-CO3). Based on the MDC, 15.2% of the patients with mitochondria-related variants were classified as “unlikely to have mitochondrial disorder”. Moreover, 4.5% of the patients with non-mitochondria-related variants and 1.43% with negative genetic tests, were classified as “probably having mitochondrial disorder”. Dual genomic sequencing in suspected MDs provided a more comprehensive and accurate diagnosis for pediatric patients, especially for patients with dual genomic variants.

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“…However, due to the variable clinical presentation of NARS2-associated disease, early sensorineural deafness can be followed by further manifestations years later into childhood. Vafaee-Shahi et al reported the cases of two siblings affected by the same missense mutation in NARS2 [ 19 ]. Both siblings were diagnosed with bilateral sensorineural hearing loss within the first 12 months of life, but one subsequently developed generalized seizures at age 14 months while the other developed the same at age seven years.…”

Section: Discussionmentioning

confidence: 99%

Bilateral Nonsyndromic Sensorineural Hearing Loss Caused by a NARS2 Mutation

Al-Sharif¹,

Alsadeq²,

Rozan³

et al. 2022

Cureus

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Mitochondrial diseases disrupt the process of energy generation by the mitochondria, leading to manifestations that can affect almost any organ in the body. Although various possible clinical phenotypes can result, neurological and neuromuscular affection is most frequently encountered. NARS2 encodes an enzyme responsible for the conjugation of asparagine to its cognate mitochondrial transfer ribonucleic acid (tRNA) molecule, representing an essential step necessary for effective mitochondrial protein synthesis. As such, mutations in this gene can lead to poor mitochondrial gene expression and, consequently, poor energy output resulting in disease. Pathogenic variants in NARS2 have been known to cause neurodegenerative and myopathic syndromes in combined oxidative phosphorylation deficiency 24 (COXPD24). However, nonsyndromic autosomal recessive deafness 94 (DFNB94), with which only one family is known to be affected, has also been reported concerning NARS2. Our report demonstrates the association of a new pathogenic variant in mitochondrial asparaginyl-tRNA synthetase (NARS2) with nonsyndromic sensorineural hearing loss, thus confirming biallelic mutations in NARS2 as a cause of nonsyndromic deafness.

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Novel phenotype and genotype spectrum of NARS2 and literature review of previous mutations

Cited by 13 publications

References 57 publications

Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations

Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations

Use of dual genomic sequencing to screen mitochondrial diseases in pediatrics: a retrospective analysis

Bilateral Nonsyndromic Sensorineural Hearing Loss Caused by a NARS2 Mutation

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