A non-coding variant in the Kozak sequence of RARS2 strongly decreases protein levels and causes pontocerebellar hypoplasia

BMC Medical Genomics

Research

Patrick Nitschké¹  Barthélémy Caron²  Antonio Rausell³  Nami Altin⁴  Sherlina Salignac⁴  Karine Siquier-Pernet⁴  Vincent Cantagrel⁴  Romain Nicolle⁵  Pierre Blanc⁶  Valérie Malan⁶  Marlène Rio⁶  Isabelle Desguerre⁷  Nathalie Boddaert⁸  Arnold Munnich⁹  Christine Bole-Feysot^1,10 

[1] Bioinformatics Core Facility, Université Paris Cité, INSERM UMR 1163, Imagine Institute, 75015, Paris, France;Clinical Bioinformatics Laboratory, Université Paris Cité, INSERM UMR 1163, Imagine Institute, 75015, Paris, France;Clinical Bioinformatics Laboratory, Université Paris Cité, INSERM UMR 1163, Imagine Institute, 75015, Paris, France;Fédération de Génétique et Médecine Génomique, Service de Médecine Génomique des Maladies Rares, AP-HP, Necker Hospital for Sick Children, 75015, Paris, France;Developmental Brain Disorders Laboratory, Université Paris Cité, INSERM UMR1163, Imagine Institute, 75015, Paris, France;Developmental Brain Disorders Laboratory, Université Paris Cité, INSERM UMR1163, Imagine Institute, 75015, Paris, France;Clinical Bioinformatics Laboratory, Université Paris Cité, INSERM UMR 1163, Imagine Institute, 75015, Paris, France;Developmental Brain Disorders Laboratory, Université Paris Cité, INSERM UMR1163, Imagine Institute, 75015, Paris, France;Fédération de Génétique et Médecine Génomique, Service de Médecine Génomique des Maladies Rares, AP-HP, Necker Hospital for Sick Children, 75015, Paris, France;Département de Neurologie Pédiatrique, AP-HP, Necker Hospital for Sick Children, 75015, Paris, France;Département de Radiologie Pédiatrique, AP-HP, Necker Hospital for Sick Children and Université Paris Cité, INSERM UMR 1163 and INSERM U1299, Imagine Institute, 75015, Paris, France;Fédération de Génétique et Médecine Génomique, Service de Médecine Génomique des Maladies Rares, AP-HP, Necker Hospital for Sick Children, 75015, Paris, France;Genomics Platform, Université Paris Cité, INSERM UMR 1163, Imagine Institute, 75015, Paris, France;

关键词: Pontocerebellar Hypoplasia;    RARS2;    Kozak;    Non-coding variant;    Bioinformatic predictions;   

DOI  :  10.1186/s12920-023-01582-z

 received in 2022-10-21, accepted in 2023-06-16,  发布年份 2023

来源: Springer

【 摘 要 】

Bi-allelic variants in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been involved in early-onset encephalopathies classified as pontocerebellar hypoplasia (PCH) type 6 and in epileptic encephalopathy. A variant (NM_020320.3:c.-2A > G) in the promoter and 5’UTR of the RARS2 gene has been previously identified in a family with PCH. Only a mild impact of this variant on the mRNA level has been detected. As RARS2 is non-dosage-sensitive, this observation is not conclusive in regard of the pathogenicity of the variant.We report and describe here a new patient with the same variant in the RARS2 gene, at the homozygous state. This patient presents with a clinical phenotype consistent with PCH6 although in the absence of lactic acidosis. In agreement with the previous study, we measured RARS2 mRNA levels in patient’s fibroblasts and detected a partially preserved gene expression compared to control. Importantly, this variant is located in the Kozak sequence that controls translation initiation. Therefore, we investigated the impact on protein translation using a bioinformatic approach and western blotting. We show here that this variant, additionally to its effect on the transcription, also disrupts the consensus Kozak sequence, and has a major impact on RARS2 protein translation. Through the identification of this additional case and the characterization of the molecular consequences, we clarified the involvement of this Kozak variant in PCH and on protein synthesis. This work also points to the current limitation in the pathogenicity prediction of variants located in the translation initiation region.

【 授权许可】

CC BY   
© The Author(s) 2023

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