Novel Biallelic NSUN3 Variants Cause Early-Onset Mitochondrial Encephalomyopathy and Seizures
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Novel Biallelic NSUN3 Variants Cause Early-Onset Mitochondrial Encephalomyopathy and Seizures Arumugam Paramasivam 1,2 & Angamuthu K. Meena 3 & Challa Venkatapathi 1 & Robert D.S. Pitceathly 4 Kumarasamy Thangaraj 1
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Received: 12 August 2019 / Accepted: 14 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Epitranscriptomic systems enable post-transcriptional modifications of cellular RNA that are essential for regulating gene expression. Of the ~ 170 known RNA chemical modifications, methylation is among the most common. Loss of function mutations in NSUN3, encoding the 5-methylcytosine (m5C) methyltransferase NSun3, have been linked to multisystem mitochondrial disease associated with combined oxidative phosphorylation deficiency. Here, we report a patient with early-onset mitochondrial encephalomyopathy and seizures in whom the novel biallelic NSUN3 missense variants c.421G>C (p.A141P) and c.454T>A (p.C152S) were detected. Segregation studies and in silico functional analysis confirmed the likely pathogenic effects of both variants. These findings expand the molecular and phenotypic spectrum of NSUN3-related mitochondrial disease. Keywords Epitranscriptomics . Mitochondrial disorders . mtDNA . NSUN3 . Encephalomyopathy . Seizures
Introduction Epitranscriptomic systems are necessary for the posttranscriptional modification of cellular RNA, RNA splicing and protein translation (Hsu et al. 2017; Rozov et al. 2016). Of the ~ 170 RNA chemical modifications reported, methylation is among the most common (Machnicka et al. 2013), with more than 90 reactions involving tRNA molecules (Boccaletto et al. 2018; Hussain et al. 2016). Numerous RNA modification enzymes and catalytic RNA-protein complexes are necessary for the post-transcriptional modification
Robert D.S. Pitceathly and Kumarasamy Thangaraj are joint senior authors for this paper.
events (Rozov et al. 2016), although many remain poorly characterised. Human diseases linked to defects in these pathways emphasise the important role of epitranscriptomics in gene expression (Hsu et al. 2017). One recent example involves the 5methylcytosine (m5C) methyltransferase NSun3, encoded by NOP2/Sun RNA methyltransferase 3 (NSUN3). Loss of function mutations in NSUN3 cause multisystem mitochondrial disease associated with a combined oxidative phosphorylation (OXPHOS) deficiency (Haag et al. 2016), highlighting the importance of NSun3 in mitochondrial translation. Here, we report novel biallelic NSUN3 missense variants in a South Asian patient with early-onset mitochondrial encephalomyopathy and seizures.
* Kumarasamy Thangaraj [email protected]
Patients and Methods
1
CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
Patient Cohort
2
BRULAC-DRC, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
3
Department of Neurology, Nizam’s Institute of Medical Sciences, Hyderabad, India
4
Department of Neuromuscular Diseases, UCL Queen Square
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