Compound heterozygosity for loss‐of‐function FARSB variants in a patient with classic features of recessive aminoacyl‐tRNA synthetase‐related disease

@article{Antonellis2018CompoundHF,
  title={Compound heterozygosity for loss‐of‐function FARSB variants in a patient with classic features of recessive aminoacyl‐tRNA synthetase‐related disease},
  author={Anthony Antonellis and Stephanie N. Oprescu and Laurie Beth Griffin and Amer Heider and Andrea Amalfitano and Jeffrey W. Innis},
  journal={Human Mutation},
  year={2018},
  volume={39},
  pages={834 - 840}
}
Aminoacyl‐tRNA synthetases (ARSs) are ubiquitously expressed enzymes that ligate amino acids onto tRNA molecules. Genes encoding ARSs have been implicated in phenotypically diverse dominant and recessive human diseases. The charging of tRNAPHE with phenylalanine is performed by a tetrameric enzyme that contains two alpha (FARSA) and two beta (FARSB) subunits. To date, mutations in the genes encoding these subunits (FARSA and FARSB) have not been implicated in any human disease. Here, we… 
Homozygosity for FARSB mutation leads to Phe‐tRNA synthetase‐related disease of growth restriction, brain calcification, and interstitial lung disease
TLDR
This study further implicates FARSB mutations in a multisystem, recessive, neurodevelopmental phenotype that share clinical features with the previously known aminoacyl‐tRNA synthetase‐related diseases.
FARS1‐related disorders caused by bi‐allelic mutations in cytosolic phenylalanyl‐tRNA synthetase genes: Look beyond the lungs!
TLDR
A multisystem clinical phenotype based on bi‐allelic mutations in the two genes (FARSA, FARSB) encoding distinct subunits for tetrameric cytosolic phenylalanyl‐tRNA synthetase (FARS1) is described and support a loss of canonical and non‐canonical function in FARS1‐associated recessive disease.
Fatal systemic disorder caused by biallelic variants in FARSA
TLDR
The pathogenicity of biallelic variants in FARSA was demonstrated and the implication of hypomorphic variants in severe phenotypes was suggested.
FARSA mutations mimic phenylalanyl‐tRNA synthetase deficiency caused by FARSB defects
TLDR
It is indicated that a disease similar to a syndrome associated with FARSB defects can also be caused by biallelic FARSA mutations, consistent with molecular structure of PheRS which is a tetramer including both FARSA and FARSB proteins.
Neuropathy‐associated histidyl‐tRNA synthetase variants attenuate protein synthesis in vitro and disrupt axon outgrowth in developing zebrafish
TLDR
The hypothesis that CMT‐HARS1 alleles exert their toxic effect in a neuronal context, and lead to dysregulated protein synthesis is supported.
Novel compound heterozygous TARS2 variants in a Chinese family with mitochondrial encephalomyopathy: a case report
TLDR
This study facilitates the understanding of combined oxidative phosphorylation deficiency disease and demonstrates that the next-generation sequencing has a high potential to study inherited disease with high phenotypic heterogeneity and genetic heterogeneity including mitochondrial diseases such as combined oxidative phosphate deficiency disease.
...
...

References

SHOWING 1-10 OF 51 REFERENCES
A Loss‐of‐Function Variant in the Human Histidyl‐tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo
TLDR
A mutation screen of the histidyl‐tRNA synthetase gene in a large cohort of patients with peripheral neuropathy revealed a rare missense variant that resides at a highly conserved amino acid, represents a loss‐of‐function allele when evaluated in yeast complementation assays, and is toxic to neurons when expressed in a worm model.
A novel multisystem disease associated with recessive mutations in the tyrosyl‐tRNA synthetase (YARS) gene
TLDR
The findings suggest the disease spectrum associated with YARS dysregulation is broader than peripheral neuropathy and may include both autosomal dominant and recessive human diseases.
Novel Compound Heterozygous Mutations Expand the Recognized Phenotypes of FARS2-Linked Disease
TLDR
The case of juvenile onset refractory epilepsy and progressive myoclonus with compound heterozygous FARS2 mutations is reported, and structure-guided analysis of the relevant mutations based on published mitochondrial phenylalanyl transfer RNA synthetase and related protein crystal structures are presented.
Mutations in methionyl-tRNA synthetase gene in a Chinese family with interstitial lung and liver disease, postnatal growth failure and anemia
TLDR
Genotype–phenotype correlation analysis suggests most of the ILLD mutations locate in the catalytic domain of MARS, and CMT2U might have different disease mechanism.
Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy.
TLDR
A new genetic cause of infantile mitochondrial Alpers encephalopathy is established and a new mitochondrial aminoacyl-tRNA synthetase as a cause of mitochondrial disease is reported.
Clinical findings in a patient with FARS2 mutations and early‐infantile‐encephalopathy with epilepsy
TLDR
A clinical report of a child with FARS2‐related disease manifesting drug‐resistant infantile spasms associated with focal seizures and he has been seizure free for the last 23 months.
A Newly Identified Missense Mutation in FARS2 Causes Autosomal‐Recessive Spastic Paraplegia
TLDR
Results indicate that a missense mutation in FARS2 contributes to HSP, which has the clinical significance of the regulation of tRNA synthetases in human neurodegenerative diseases.
...
...