Novel FARS2 variants in patients with early onset encephalopathy with or without epilepsy associated with long survival

Barcia, Giulia; Rio, Marlène; Assouline, Zahra; Zangarelli, Coralie; Roux, Charles‐Joris; Lonlay, Pascale de; Steffann, Julie; Desguerre, Isabelle; Münnich, Arnold; Bonnefont, Jean‐Paul; Boddaert, Nathalie; Rötig, Agnès; Metodiev, Metodi D.; Ruzzenente, Benedetta

doi:10.1038/s41431-020-00757-x

Cited by 8 publications

(15 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to their canonical roles, the mt-aaRSs are hypothesized to have functions in monitoring of amino acid levels, as sensors for the mitochondrial environment, and transcriptional regulation [87] and through the addition of new protein domains have been associated with neural development and immune response, among others, as reviewed by [89]. The FARS2 gene produces the mt-PheRS protein (phenylalanyl-tRNA synthetase) which is mitochondria-locating and responsible for attaching phenylalanine to its corresponding mt-tRNA for mitochondrial protein translation [90]. Intragenic variants in the FARS2 gene have been linked to two primary clinical manifestations, early-onset epileptic mitochondrial encephalopathy and spastic paraplegia, and for patients in both groups symptoms can also include intellectual disability or developmental delay [90].…”

Section: Discussionmentioning

confidence: 99%

“…The FARS2 gene produces the mt-PheRS protein (phenylalanyl-tRNA synthetase) which is mitochondria-locating and responsible for attaching phenylalanine to its corresponding mt-tRNA for mitochondrial protein translation [90]. Intragenic variants in the FARS2 gene have been linked to two primary clinical manifestations, early-onset epileptic mitochondrial encephalopathy and spastic paraplegia, and for patients in both groups symptoms can also include intellectual disability or developmental delay [90]. Deletions within FARS2 and reduced expression levels have also been associated with schizophrenia [91].…”

Section: Discussionmentioning

confidence: 99%

“…to two primary clinical manifestations, early-onset epileptic mitochondrial encephalopathy and spastic paraplegia, and for patients in both groups symptoms can also include intellectual disability or developmental delay [90]. Deletions within FARS2 and reduced expression levels have also been associated with schizophrenia [91].…”

Section: Db Tf Target Genes Are Expressed In Oligodendrocytes Testis/...mentioning

confidence: 99%

See 2 more Smart Citations

Evolution is in the details: Regulatory differences in modern human and Neanderthal

Barker

Parkkila

Tolvanen

2020

Preprint

View full text Add to dashboard Cite

Transcription factor (TF) proteins play a critical role in the regulation of eukaryote gene expression by sequence-specific binding to genomic locations known as transcription factor binding sites. Here we present the TFBSFootprinter tool which has been created to combine transcription-relevant data from six large empirical datasets: Ensembl, JASPAR, FANTOM5, ENCODE, GTEX, and GTRD to more accurately predict functional sites. A complete analysis integrating all experimental datasets can be performed on genes in the human genome, and a limited analysis can be done on a total of 125 vertebrate species. As a use-case, we have used TFBSFootprinter to study sites of genomic variation between modern humans and Neandertal promoters. We found significant differences in binding affinity for 86 transcription factors, groups of which are both highly expressed, and show correlation of expression, in immune cells and adult and developing neural tissues.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Db Tf Target Genes Are Expressed In Oligodendrocytes Testis/...mentioning

confidence: 99%

See 1 more Smart Citation

Evolution is in the details: Regulatory differences in modern human and Neanderthal

Barker

Parkkila

Tolvanen

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…COXPD14 is an unusual autosomal recessive disorder caused by defects in FARS2 and is characterized by early-onset encephalopathy with or without epilepsy, developmental delay, high levels of lactate, and short or long lifetimes [ 15 ]. The first FARS2 variant p.Tyr144Cys was reported by Shamseldin et al .…”

Section: Discussionmentioning

confidence: 99%

“…Barcia et al . have described three early-onset patients with or without epileptic seizures, all of whom had longer lifespans and they were still alive at the time of the study, which highlighted that not all patients with early-onset form experience seizures or have poor outcomes [ 15 ]. To date, COXPD14 with juvenile-onset epilepsy was found in only three individuals.…”

Section: Discussionmentioning

confidence: 99%

Two Chinese siblings of combined oxidative phosphorylation deficiency 14 caused by compound heterozygous variants in FARS2

Wang

et al. 2022

Eur J Med Res

View full text Add to dashboard Cite

Background As a rare mitochondrial disease, combined oxidative phosphorylation deficiency 14 (COXPD14) is caused by biallelic variants in the phenylalanyl-tRNA synthetase 2, mitochondrial gene (FARS2) with clinical features of developmental delay, an elevated lactate level, early-onset encephalopathy, liver failure, and hypotonia. The objectives of this study were to analyze the clinical and molecular features of two Chinese siblings affected with COXPD14, and to review relevant literature. Methods Mutation screening was performed by whole exome sequencing (WES) in combination with Sanger sequencing validation to identify the disease-causing variants of the two patients. Results The two siblings presented with severe clinical features and both progressed aggressively and failed to survive after treatment abandonment. We identified two compound heterozygous FARS2 variants c.925G>A p.Gly309Ser and c.943G>C p.Gly315Arg in this proband, which were inherited from the unaffected father and mother, respectively. In addition, Sanger sequencing confirmed that the elder affected sister carried the same compound heterozygous variants. The c.925G>A p.Gly309Ser variant is known and commonly reported in COXPD14 patients, while c.943G>C p.Gly315Arg is a novel one. Neither of the variants was found in 100 Chinese healthy controls. Both variants were classified as “deleterious” and were located in the highly conserved regions of the protein. The above results suggested that the two variants were likely causative in this COXPD14-affected pedigree. Conclusions Our study expands the mutation spectrum of FARS2 and highlights the importance of genetic testing in the diagnosis of diseases with a wide variety of phenotypes, especially in the differential diagnosis of diseases.

show abstract

Ataxia and spastic paraplegia in mitochondrial disease

Synofzik¹,

Rugarli²,

Reid³

et al. 2023

Handbook of Clinical Neurology

View full text Add to dashboard Cite

Novel FARS2 variants in patients with early onset encephalopathy with or without epilepsy associated with long survival

Abstract: doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Cited by 8 publications

References 19 publications

Evolution is in the details: Regulatory differences in modern human and Neanderthal

Evolution is in the details: Regulatory differences in modern human and Neanderthal

Two Chinese siblings of combined oxidative phosphorylation deficiency 14 caused by compound heterozygous variants in FARS2

Ataxia and spastic paraplegia in mitochondrial disease

Contact Info

Product

Resources

About