• IARS1
• aminoacyl‐tRNA synthetase
• aminoacyl‐tRNA synthetase deficiencies
• growth retardation, impaired intellectual development, hypotonia, and hepatopathy
• immune dysregulation
• isoleucine

• R35 GM136441 NIGMS NIH HHS
• National Institute of General Medical Sciences

• ARS1‐deficiency
• amino acid supplementation
• natural history
• symptoms
• treatment effects

• Humans
• Amino Acyl-tRNA Synthetases/deficiency
• Amino Acyl-tRNA Synthetases/genetics
• Phenotype
• Microcephaly
• Amino Acids/therapeutic use
• Seizures

• IARS1 gene
• case repoort
• gene muatation
• infant
• pulmonary alveolar proteinosis (PAP)

• CALFAN
• ILFS2
• ILFS3
• NBAS
• RINT1
• SCYL1
• disorders of vesicular trafficking
• pediatric acute liver failure
• recurrent acute liver failure

• Humans
• Liver Failure, Acute/genetics
• Liver Failure, Acute/etiology
• Liver Failure, Acute/metabolism
• Membrane Proteins/genetics
• Membrane Proteins/deficiency
• Neoplasm Proteins

• 01GM1906B Bundesministerium für Bildung und Forschung
• Bundesministerium für Bildung und Forschung

• structural biology
• biochemistry

• Saccharomyces cerevisiae/genetics
• Saccharomyces cerevisiae/metabolism
• Isoleucine-tRNA Ligase/metabolism
• Isoleucine-tRNA Ligase/genetics
• Isoleucine-tRNA Ligase/chemistry
• Aminoacylation
• Saccharomyces cerevisiae Proteins/metabolism
• Saccharomyces cerevisiae Proteins/genetics
• Saccharomyces cerevisiae Proteins/chemistry
• Hydrogen Bonding
• Transfer RNA Aminoacylation
• RNA, Transfer, Ile/metabolism
• RNA, Transfer, Ile/chemistry
• RNA, Transfer, Ile/genetics
• Substrate Specificity
• Nucleotides/metabolism
• Crystallography, X-Ray
• Models, Molecular
• Arginine/metabolism
• Arginine/chemistry

• 22207133 National Natural Science Foundation of China (National Science Foundation of China)

• Mendelian disease
• aminoacyl-tRNA synthetases
• protein translation
• recessive disease
• threonine
• threonyl-tRNA synthetase

• Animals
• Mice
• Caenorhabditis elegans/genetics
• Saccharomyces cerevisiae/genetics
• Threonine-tRNA Ligase/genetics
• Threonine-tRNA Ligase/metabolism
• Humans
• Phenotype
• Loss of Function Mutation
• Disease Models, Animal
• Mutation, Missense

• P30 AR075043 NIAMS NIH HHS
• R35 GM136441 NIGMS NIH HHS
• T32 GM007544 NIGMS NIH HHS

• IARS1
• IARS2
• aminoacyl-tRNA
• mitochondrial disease

• Humans
• Animals
• Mutation
• Mitochondrial Diseases/genetics
• Mitochondrial Diseases/pathology
• Isoleucine-tRNA Ligase/genetics
• Cattle
• Mitochondria/genetics
• Mice

• R35 GM136441 NIGMS NIH HHS
• F31 NS108510 NINDS NIH HHS
• R01 GM024872 NIGMS NIH HHS
• T32 GM007544 NIGMS NIH HHS
• P30 CA046592 NCI NIH HHS
• P30 AR075043 NIAMS NIH HHS

• IARS1 gene
• bioinformatics analysis
• developmental regression
• genetics analysis
• global developmental delay

• Child
• Humans
• Female
• Infant
• Developmental Disabilities/genetics
• Phenotype
• Epilepsy/genetics
• Seizures
• China

• no.2021SYS24 Medical Genetics Research Committee Key Laboratory of Shanxi Province "2021 "Four Batch" Science and Technology Innovation Program"
• no.2023016 Shanxi Province Health and Wellness Committee Funded Project
• no.2005DKA32408 the National Population and Reproductive Health Science Data Center of China

• hepatic triglyceride
• mitochondrial diseases
• serum ornithine carbamoyltransferase
• weak calf syndrome

Aminoacyl tRNA transferases play an essential role in protein biosynthesis, and variants of these enzymes result in various human diseases. FARSA, which encodes the α subunit of cytosolic phenylalanyl-tRNA synthetase, was recently reported as a suspected causal gene for multiorgan disorder. This study aimed to validate the pathogenicity of variants in the FARSA gene.

Exome sequencing revealed novel compound heterozygous variants in FARSA, P347L and R475Q, from a patient who initially presented neonatal-onset failure to thrive, liver dysfunction, and frequent respiratory infections. His developmental milestones were nearly arrested, and the patient died at 28 months of age as a result of progressive hepatic and respiratory failure. The P347L variant was predicted to disrupt heterodimer interaction and failed to form a functional heterotetramer by structural and biochemical analyses. R475 is located at a highly conserved site and is reported to be involved in phenylalanine activation and transfer to tRNA. The R475Q mutant FARSA were co-purified with FARSB, but the mutant enzyme showed an approximately 36% reduction in activity in our assay relative to the wild-type protein. Additional functional analyses on variants from previous reports (N410K, F256L, R404C, E418D, and F277V) were conducted. The R404C variant from a patient waiting for organ transplantation also failed to form tetramers but the E418D, N410K, F256L, and F277V variants did not affect tetramer formation. In the functional assay, the N410K located at the phenylalanine-binding site exhibited no catalytic activity, whereas other variants (E418D, F256L and F277V) exhibited lower ATPase activity than wild-type FARSA at low phenylalanine concentrations.

Our data demonstrated the pathogenicity of biallelic variants in FARSA and suggested the implication of hypomorphic variants in severe phenotypes.

The online version contains supplementary material available at 10.1186/s13023-022-02457-9.

• Aminoacyl-tRNA synthetase
• FARSA
• Phenylalanyl-tRNA synthetase

• Case report
• Growth retardation
• IARS1
• Recurrent liver failure
• Variations

• Aminoacyl-tRNA synthetases (ARS1)
• Functional protein domains
• Multisystem diseases
• Neurodevelopmental disorders
• Novel disease genes
• Phenotypic heterogeneity

• Adolescent
• Child
• Child, Preschool
• Female
• Humans
• Male
• Mutation, Missense
• Neurodevelopmental Disorders/genetics
• Phenotype
• Protein Conformation
• Tyrosine-tRNA Ligase/chemistry
• Tyrosine-tRNA Ligase/genetics
• Exome Sequencing

• MR/S005021/1 Medical Research Council
• Deutsche Forschungsgemeinschaft
• Bundesministerium für Bildung und Forschung
• Heinrich-Heine-Universität Düsseldorf (3102)

• Aminoacylation
• Developmental delay
• Exome sequencing
• Hepatic cirrhosis
• Intestinal lung disease
• YARS1

• Developmental Disabilities/genetics
• Developmental Disabilities/pathology
• Failure to Thrive/genetics
• Failure to Thrive/pathology
• Female
• Humans
• Infant
• Liver Diseases/genetics
• Liver Diseases/pathology
• Loss of Function Mutation
• Lung Diseases/genetics
• Lung Diseases/pathology
• Tyrosine-tRNA Ligase/genetics

Recessive cytosolic aminoacyl-tRNA synthetase (ARS) deficiencies are severe multiorgan diseases, with limited treatment options. By loading transfer RNAs (tRNAs) with their cognate amino acids, ARS are essential for protein translation. However, it remains unknown why ARS deficiencies lead to specific symptoms, especially early life and during infections. We set out to increase pathophysiological insight and improve therapeutic possibilities.

In fibroblasts from patients with isoleucyl-RS (IARS), leucyl-RS (LARS), phenylalanyl-RS-beta-subunit (FARSB), and seryl-RS (SARS) deficiencies, we investigated aminoacylation activity, thermostability, and sensitivity to ARS-specific amino acid concentrations, and developed personalized treatments.

Aminoacylation activity was reduced in all patients, and further diminished at 38.5/40 °C (P^LARS and P^FARSB), consistent with infectious deteriorations. With lower cognate amino acid concentrations, patient fibroblast growth was severely affected. To prevent local and/or temporal deficiencies, we treated patients with corresponding amino acids (follow-up: 1/2–2 2/3rd years), and intensified treatment during infections. All patients showed beneficial treatment effects, most strikingly in growth (without tube feeding), head circumference, development, coping with infections, and oxygen dependency.

For these four ARS deficiencies, we observed a common disease mechanism of episodic insufficient aminoacylation to meet translational demands and illustrate the power of amino acid supplementation for the expanding ARS patient group. Moreover, we provide a strategy for personalized preclinical functional evaluation.

Aminoacyl-tRNA synthetases (ARSs) are crucial enzymes for protein translation. Mutations in genes encoding ARSs are associated with human disease. Tyrosyl-tRNA synthetase is encoded by YARS which is ubiquitously expressed and implicated in an autosomal dominant form of Charcot-Marie-Tooth and autosomal recessive YARS-related multisystem disease.

We report on a former 34-week gestational age male who presented at 2 months of age with failure to thrive (FTT) and cholestatic hepatitis. He was subsequently diagnosed with hyperinsulinemic hypoglycemia with a negative congenital hyperinsulinism gene panel and F-DOPA positron-emission tomography (PET) scan that did not demonstrate a focal lesion. Autopsy findings were notable for overall normal pancreatic islet size and morphology. Trio whole exome sequencing identified a novel homozygous variant of uncertain significance in YARS (c.611A > C, p.Tyr204Cys) with each parent a carrier for the YARS variant. Euglycemia was maintained with diazoxide (max dose, 18 mg/kg/day), and enteral dextrose via gastrostomy tube (G-Tube). During his prolonged hospitalization, the patient developed progressive liver disease, exocrine pancreatic insufficiency, acute renal failure, recurrent infections, ichthyosis, hematologic concerns, hypotonia, and global developmental delay. Such multisystem features have been previously reported in association with pathogenic YARS mutations. Although hypoglycemia has been associated with pathogenic YARS mutations, this report provides more conclusive data that a YARS variant can cause hyperinsulinemic hypoglycemia. This case expands the allelic and clinical heterogeneity of YARS-related disease. In addition, YARS-related disease should be considered in the differential of hyperinsulinemic hypoglycemia associated with multisystem disease.

• Chronic liver disease
• YARS
• hyperinsulinemic hypoglycemia
• multisystem disease
• tyrosyl-tRNA synthetase

• alternative splicing
• cholangiocarcinoma
• genomic instability
• immunotherapy
• overall survival

Aminoacyl tRNA synthetases/ligases (ARSs) are highly conserved enzymes involved in attaching amino acids to tRNA promoting protein synthesis. Although deficiencies of ARSs localized to the mitochondria classically present with neuropathology, the clinical features of cytosolic ARS deficiencies are more variable. They have previously been associated with neonatal hepatitis, but never with early-onset inflammatory bowel disease.

A nine-year-old Bangladeshi boy presented with neonatal liver failure and deranged clotting, transaminitis and cholestasis. His parents were first cousins. Two older brothers and a sister were well. The patient suffered from loose stools from early infancy which became more troublesome and persistent from five years old with ten bloody motions a day. Repeated endoscopies showed persistent pancolitis, which was refractory to mesalazine, corticosteroids, azathioprine, sirolimus and anti-TNF (adalimumab) therapy, but has improved recently with subcutaneous methotrexate.Whole Genome Sequencing revealed a novel pathogenic missense variant (c.290A > G) in the cytosolic isoleucyl-tRNA synthetase gene, leading to an amino acid substitution (p.Asp97Gly). Pathogenic variants in other genes associated with inflammatory bowel disease (IBD) (ADAM17, EGFR, FOXP3, IL10RA, IL10RB, IL21R, NCF4, STAT3) were excluded. Cytokine assays demonstrated markedly elevated IL-2, IL-5, IL-13, IL-9 and IL-10 by the patient’s CD4⁺ T-cells, while IL-17A, IL-17F, IFNβ were lower, and TNFα not significantly different when compared to healthy controls.

This case report provides evidence that recessive mutations in cytosolic isoleucyl-tRNA synthetase are a novel monogenic cause of IBD, which should be considered, particularly in infants and children with a history of neonatal hepatitis and very early-onset IBD poorly responsive to treatment.

• Inflammatory bowel disease
• Hepatitis
• Gene
• Cytosolic isoleucine tRNA synthase

• Age of Onset
• Biopsy
• Child
• Colon/pathology
• Drug Resistance/genetics
• Humans
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/pathology
• Intestinal Mucosa/pathology
• Isoleucine-tRNA Ligase/deficiency
• Isoleucine-tRNA Ligase/genetics
• Male
• Mutation

• aminoacyl-tRNA synthetase
• cysteinyl-tRNA synthetase
• developmental delay
• microcephaly
• peripheral neuropathy
• recessive disease

• Adult
• Amino Acid Sequence
• Amino Acyl-tRNA Synthetases/genetics
• Charcot-Marie-Tooth Disease/enzymology
• Charcot-Marie-Tooth Disease/etiology
• Charcot-Marie-Tooth Disease/pathology
• Developmental Disabilities/enzymology
• Developmental Disabilities/etiology
• Developmental Disabilities/pathology
• Female
• Genes, Recessive
• Genetic Predisposition to Disease
• Hair Diseases/enzymology
• Hair Diseases/etiology
• Hair Diseases/pathology
• Humans
• Male
• Microcephaly/enzymology
• Microcephaly/etiology
• Microcephaly/pathology
• Mutation
• Nail Diseases/enzymology
• Nail Diseases/etiology
• Nail Diseases/pathology
• Pedigree
• Phenotype
• Prognosis
• Sequence Homology
• Young Adult

• R01 GM114343 NIGMS NIH HHS
• U01 GM108972 NIGMS NIH HHS
• F31 NS108510 NINDS NIH HHS
• T32 GM007863 NIGMS NIH HHS
• R01 GM108972 NIGMS NIH HHS
• R01 GM126210 NIGMS NIH HHS
• T32 GM007544 NIGMS NIH HHS
• F31 NS113515 NINDS NIH HHS
• R01 GM118647 NIGMS NIH HHS
• T32 GM007315 NIGMS NIH HHS

• gene mutation
• growth retardation
• hepatopathy
• intellectual disability
• joint contracture
• whole genome resequencing

• Abnormalities, Multiple
• Child
• Child, Preschool
• Contracture/complications
• Contracture/genetics
• Female
• Filaggrin Proteins
• Genome-Wide Association Study
• Growth Disorders/complications
• Growth Disorders/genetics
• Humans
• Infant
• Infant, Newborn
• Intellectual Disability/complications
• Intellectual Disability/genetics
• Liver Diseases/complications
• Liver Diseases/genetics
• Male
• Mutation
• Sequence Analysis, DNA

• bi-allelic mutation
• cerebral calcifications
• cholesterol pneumonitis
• exome sequencing
• interstitial lung disease
• missense mutation
• multi-system disease
• non-canonical function
• non-coding variant
• tRNA synthetase

• Adolescent
• Alleles
• Amino Acyl-tRNA Synthetases/genetics
• Charcot-Marie-Tooth Disease/genetics
• Child, Preschool
• Female
• Genes, Recessive/genetics
• Heterozygote
• Humans
• Infant
• Lung Diseases/genetics
• Male
• Mutation/genetics
• Protein Biosynthesis/genetics

• Wellcome Trust
• G0800674 Medical Research Council
• R01 GM088278 NIGMS NIH HHS

Pathogenic variations in genes encoding aminoacyl-tRNA synthetases (ARSs) are increasingly associated with human disease. Clinical features of autosomal recessive ARS deficiencies appear very diverse and without apparent logic. We searched for common clinical patterns to improve disease recognition, insight into pathophysiology, and clinical care.

Symptoms were analyzed in all patients with recessive ARS deficiencies reported in literature, supplemented with unreported patients evaluated in our hospital.

In literature, we identified 107 patients with AARS, DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies. Common symptoms (defined as present in ≥4/13 ARS deficiencies) included abnormalities of the central nervous system and/or senses (13/13), failure to thrive, gastrointestinal symptoms, dysmaturity, liver disease, and facial dysmorphisms. Deep phenotyping of 5 additional patients with unreported compound heterozygous pathogenic variations in IARS, LARS, KARS, and QARS extended the common phenotype with lung disease, hypoalbuminemia, anemia, and renal tubulopathy.

We propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.

• Aminoacyl-tRNA synthetase deficiency
• Clinical phenotype
• Cytosolic translation

Aminoacyl‐tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNAs with their cognate amino acids, therefore essential for the first step in protein synthesis. Although the majority of protein synthesis happens in the cytosol, an additional translation apparatus is required to translate the 13 mitochondrial DNA‐encoded proteins important for oxidative phosphorylation. Most ARS genes in these cellular compartments are distinct, but two genes are common, encoding aminoacyl‐tRNA synthetases of glycine (GARS) and lysine (KARS) in both mitochondria and the cytosol. Mutations in the majority of the 37 nuclear‐encoded human ARS genes have been linked to a variety of recessive and dominant tissue‐specific disorders. Current data indicate that impaired enzyme function could explain the pathogenicity, however not all pathogenic ARSs mutations result in deficient catalytic function; thus, the consequences of mutations may arise from other molecular mechanisms. The peripheral nerves are frequently affected, as illustrated by the high number of mutations in cytosolic and bifunctional tRNA synthetases causing Charcot–Marie–Tooth disease (CMT). Here we provide insights on the pathomechanisms of CMT‐causing tRNA synthetases with specific focus on the two bifunctional tRNA synthetases (GARS, KARS).

• Charcot-Marie-Tooth disease
• aminoacyl-tRNA synthetases
• cytosolic and mitochondrial translation

• Alleles
• Amino Acyl-tRNA Synthetases/genetics
• Amino Acyl-tRNA Synthetases/metabolism
• Amino Acyl-tRNA Synthetases/physiology
• Genes, Dominant/genetics
• Genes, Recessive/genetics
• Heterozygote
• Humans
• Mutation
• Phenotype
• Protein Biosynthesis/genetics

• F31 NS108510 NINDS NIH HHS
• R01 GM118647 NIGMS NIH HHS
• T32 GM007544 NIGMS NIH HHS