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Clinical and molecular characterization of novel FARS2 variants causing neonatal mitochondrial disease

Lookup NU author(s): Dr Kyle Thompson, Dr Langping He, Professor Zofia Chrzanowska-LightowlersORCiD, Professor Robert Taylor


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© 2023 Elsevier Inc.FARS2 encodes the mitochondrial phenylalanyl-tRNA synthetase (mtPheRS), which is essential for charging mitochondrial (mt-) tRNAPhe with phenylalanine for use in intramitochondrial translation. Many biallelic, pathogenic FARS2 variants have been described previously, which are mostly associated with two distinct clinical phenotypes; an early onset epileptic mitochondrial encephalomyopathy or a later onset spastic paraplegia. In this study, we report on a patient who presented at 3 weeks of age with tachypnoea and poor feeding, which progressed to severe metabolic decompensation with lactic acidosis and seizure activity followed by death at 9 weeks of age. Rapid trio whole exome sequencing identified compound heterozygous FARS2 variants including a pathogenic exon 2 deletion on one allele and a rare missense variant (c.593G > T, p.(Arg198Leu)) on the other allele, necessitating further work to aid variant classification. Assessment of patient fibroblasts demonstrated severely decreased steady-state levels of mtPheRS, but no obvious defect in any components of the oxidative phosphorylation system. To investigate the potential pathogenicity of the missense variant, we determined its high-resolution crystal structure, demonstrating a local structural destabilization in the catalytic domain. Moreover, the R198L mutation reduced the thermal stability and impaired the enzymatic activity of mtPheRS due to a lower binding affinity for tRNAPhe and a slower turnover rate. Together these data confirm the pathogenicity of this FARS2 variant in causing early-onset mitochondrial epilepsy.

Publication metadata

Author(s): Chen W, Rehsi P, Thompson K, Yeo M, Stals K, He L, Schimmel P, Chrzanowska-Lightowlers ZMA, Wakeling E, Taylor RW, Kuhle B

Publication type: Article

Publication status: Published

Journal: Molecular Genetics and Metabolism

Year: 2023

Volume: 140

Issue: 3

Print publication date: 01/11/2023

Online publication date: 24/07/2023

Acceptance date: 22/07/2023

ISSN (print): 1096-7192

ISSN (electronic): 1096-7206

Publisher: Academic Press Inc.


DOI: 10.1016/j.ymgme.2023.107657

PubMed id: 37523899


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