Research

Our research focuses on elucidating the disease mechanism of aminacyl-tRNA synthetase (aARS) deficiencies, as well as development of new diagnostic tools and improvement of therapeutic options.

Our recent articles

  1. Kok G, Tseng LA, Schene IF, et al. Treatment of ARS-deficiencies with specific amino acids. Genet Med. 2021. Epub ahead of print.
  2. Kok G, van Karnebeek CDM, Fuchs SA. Response to Shen and Zou. Genet Med. 2021;23(3):589-590.
  3. Fuchs SA, Schene IF, Kok G, et al. Aminoacyl-tRNA synthetase deficiencies in search of common themes. Genet Med. 2019;21(2):319-330.

Cases of cytosolic aARS deficiencies in literature

Last updated: 18 May 2021

AARS1

  1. Simons C, Griffin LB, Helman G, et al. Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect. Am J Hum Genet. 2015;96(4):675-681.
  2. Nakayama T, Wu J, Galvin-Parton P, et al. Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy. Hum Mutat. 2017;38(10):1348-1354.
  3. Marten LM, Brinkert F, Smith DEC, Prokisch H, Hempel M, Santer R. Recurrent acute liver failure in alanyl-tRNA synthetase-1 (AARS1) deficiency. Mol Genet Metab Reports. 2020;25:100681.

CARS1

  1. Kuo ME, Theil AF, Kievit A, et al. Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails. Am J Hum Genet. 2019;104(3):520-529.

DARS1

  1. Taft RJ, Vanderver A, Leventer RJ, et al. Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity. Am J Hum Genet. 2013;92(5):774-780.

FARSA

  1. Krenke K, Szczałuba K, Bielecka T, et al. FARSA mutations mimic phenylalanyl-tRNA synthetase deficiency caused by FARSB defects. Clin Genet. 2019;96(5):468-472.
  2. Schuch LA, Forstner M, Rapp CK, et al. FARS1-related disorders caused by bi-allelic mutations in cytosolic phenylalanyl-tRNA synthetase genes: Look beyond the lungs! Clin Genet. 2021;99(6):789-801.

FARSB

  1. Antonellis A, Oprescu SN, Griffin LB, Heider A, Amalfitano A, Innis JW. Compound heterozygosity for loss-of-function FARSB variants in a patient with classic features of recessive aminoacyl-tRNA synthetase-related disease. Hum Mutat. 2018;39(6):834-840.
  2. Zadjali F, Al-Yahyaee A, Al-Nabhani M, et al. Homozygosity for FARSB mutation leads to Phe-tRNA synthetase-related disease of growth restriction, brain calcification, and interstitial lung disease. Hum Mutat. 2018;39(10):1355-1359.
  3. Xu Z, Lo W-S, Beck DB, et al. Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function. Am J Hum Genet. 2018;103(1):100-114.
  4. Schuch LA, Forstner M, Rapp CK, et al. FARS1-related disorders caused by bi-allelic mutations in cytosolic phenylalanyl-tRNA synthetase genes: Look beyond the lungs! Clin Genet. 2021;99(6):789-801.
  5. Kok G, Tseng LA, Schene IF, et al. Treatment of ARS-deficiencies with specific amino acids. Genet Med. 2021. Epub ahead of print.

GARS1

  1. McMillan HJ, Schwartzentruber J, Smith A, et al. Compound heterozygous mutations in glycyl-tRNA synthetase are a proposed cause of systemic mitochondrial disease. BMC Med Genet. 2014;15(1):36.
  2. Nafisinia M, Riley LG, Gold WA, et al. Compound heterozygous mutations in glycyl-tRNA synthetase (GARS) cause mitochondrial respiratory chain dysfunction. Reddy H, ed. PLoS One. 2017;12(6):e0178125.
  3. Oprescu SN, Chepa-Lotrea X, Takase R, et al. Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation. Hum Mutat. 2017;38(10):1412-1420.

HARS1

  1. Puffenberger EG, Jinks RN, Sougnez C, et al. Genetic mapping and exome sequencing identify variants associated with five novel diseases. Janecke AR, ed. PLoS One. 2012;7(1):e28936.
  2. Galatolo D, Kuo ME, Mullen P, et al. Bi-allelic mutations in HARS1 severely impair histidyl-tRNA synthetase expression and enzymatic activity causing a novel multisystem ataxic syndrome. Hum Mutat. 2020;41(7):1232-1237.

IARS1

  1. Kopajtich R, Murayama K, Janecke AR, et al. Biallelic IARS Mutations Cause Growth Retardation with Prenatal Onset, Intellectual Disability, Muscular Hypotonia, and Infantile Hepatopathy. Am J Hum Genet. 2016;99(2):414-422.
  2. Orenstein N, Weiss K, Oprescu SN, et al. Bi-allelic IARS mutations in a child with intra-uterine growth retardation, neonatal cholestasis, and mild developmental delay. Clin Genet. 2017;91(6):913-917.
  3. Fuchs SA, Schene IF, Kok G, et al. Aminoacyl-tRNA synthetase deficiencies in search of common themes. Genet Med. 2019;21(2):319-330.
  4. Fagbemi A, Newman WG, Tangye SG, Hughes SM, Cheesman E, Arkwright PD. Refractory very early-onset inflammatory bowel disease associated with cytosolic isoleucyl-tRNA synthetase deficiency: A case report. World J Gastroenterol. 2020;26(15):1841-1846.

KARS1

  1. Santos-Cortez RLP, Lee K, Azeem Z, et al. Mutations in KARS, encoding Lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89. Am J Hum Genet. 2013;93(1):132-140.
  2. McMillan HJ, Humphreys P, Smith A, et al. Congenital Visual Impairment and Progressive Microcephaly Due to Lysyl–Transfer Ribonucleic Acid (RNA) Synthetase ( KARS ) Mutations. J Child Neurol. 2015;30(8):1037-1043.
  3. Verrigni D, Diodato D, Di Nottia M, et al. Novel mutations in KARS cause hypertrophic cardiomyopathy and combined mitochondrial respiratory chain defect. Clin Genet. 2017;91(6):918-923.
  4. Ruzzenente B, Assouline Z, Barcia G, et al. Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(Pro228Leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis. Hum Mutat. 2018;39(12):2047-2059.
  5. 1. Van Der Knaap MS, Bugiani M, Mendes MI, et al. Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy. Neurology. 2019;92(11):E1225-E1237.
  6. Fuchs SA, Schene IF, Kok G, et al. Aminoacyl-tRNA synthetase deficiencies in search of common themes. Genet Med. 2019;21(2):319-330.
  7. Scheidecker S, Bär S, Stoetzel C, et al. Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy. Hum Mutat. 2019;40(10):1826-1840.

LARS1

  1. Casey JP, McGettigan P, Lynam-Lennon N, et al. Identification of a mutation in LARS as a novel cause of infantile hepatopathy. Mol Genet Metab. 2012;106(3):351-358.
  2. Casey JP, Slattery S, Cotter M, et al. Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS. J Inherit Metab Dis. 2015;38(6):1085-1092.
  3. Peroutka C, Salas J, Britton J, et al. Severe neonatal manifestations of infantile liver failure syndrome type 1 caused by cytosolic leucine-tRNA synthetase deficiency. JIMD Reports. 2019;45:71-76.
  4. Fuchs SA, Schene IF, Kok G, et al. Aminoacyl-tRNA synthetase deficiencies in search of common themes. Genet Med. 2019;21(2):319-330.
  5. Tabolacci E, Molinario C, Marangi G, et al. Infantile Liver Failure Syndrome 1 associated with a novel variant of the LARS1 gene: Clinical, genetic, and functional characterization. Clin Genet. 2021;99(4):601-603.
  6. Lenz D, Smith DEC, Crushell E, et al. Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants in LARS1. Genet Med. 2020;22(11):1863-1873.

MARS1

  1. van Meel E, Wegner DJ, Cliften P, et al. Rare recessive loss-of-function methionyl-tRNA synthetase mutations presenting as a multi-organ phenotype. BMC Med Genet. 2013;14(1):106.
  2. Hadchouel A, Wieland T, Griese M, et al. Biallelic mutations of methionyl-tRNA synthetase cause a specific type of pulmonary alveolar proteinosis prevalent on Réunion Island. Am J Hum Genet. 2015;96(5):826-831.
  3. Sun Y, Hu G, Luo J, et al. Mutations in methionyl-tRNA synthetase gene in a Chinese family with interstitial lung and liver disease, postnatal growth failure and anemia. J Hum Genet. 2017;62(6):647-651.
  4. Abuduxikuer K, Feng JY, Lu Y, Xie XB, Chen L, Wang JS. Novel methionyl-tRNA synthetase gene variants/ phenotypes in interstitial lung and liver disease: A case report and review of literature. World J Gastroenterol. 2018;24(36):4208-4216.
  5. Alzaid M, Alshamrani A, Harbi ASA, Alenzi A, Mohamed S. Methionyl-tRNA synthetase novel mutation causes pulmonary alveolar proteinosis. Saudi Med J. 2019;40(2):195-198.
  6. Lenz D, Stahl M, Seidl E, et al. Rescue of respiratory failure in pulmonary alveolar proteinosis due to pathogenic MARS1 variants. Pediatr Pulmonol. 2020;55(11):3057-3066.

NARS1

  1. Manole A, Efthymiou S, O’Connor E, et al. De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects. Am J Hum Genet. 2020;107(2):311-324.

QARS1

  1. Zhang X, Ling J, Barcia G, et al. Mutations in QARS, encoding glutaminyl-trna synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. Am J Hum Genet. 2014;94(4):547-558.
  2. Salvarinova R, Ye CX, Rossi A, et al. Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities. Neurogenetics. 2015;16(2):145-149.
  3. Kodera H, Osaka H, Iai M, et al. Mutations in the glutaminyl-tRNA synthetase gene cause early-onset epileptic encephalopathy. J Hum Genet. 2015;60(2):97-101.
  4. Leshinsky-Silver E, Ling J, Wu J, et al. Severe growth deficiency, microcephaly, intellectual disability, and characteristic facial features are due to a homozygous QARS mutation. Neurogenetics. 2017;18(3):141-146.
  5. Johannesen KM, Mitter D, Janowski R, et al. Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy. Neurol Genet. 2019;5(6):e373.
  6. Fuchs SA, Schene IF, Kok G, et al. Aminoacyl-tRNA synthetase deficiencies in search of common themes. Genet Med. 2019;21(2):319-330.

RARS1

  1. Wolf NI, Salomons GS, Rodenburg RJ, et al. Mutations in RARS cause hypomyelination. Ann Neurol. 2014;76(1):134-139.
  2. Mendes MI, Green LMC, Bertini E, et al. RARS1-related hypomyelinating leukodystrophy: Expanding the spectrum. Ann Clin Transl Neurol. 2020;7(1):83-93.

SARS1

  1. Musante L, Püttmann L, Kahrizi K, et al. Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability. Hum Mutat. 2017;38(6):621-636.
  2. Kok G, Tseng LA, Schene IF, et al. Treatment of ARS-deficiencies with specific amino acids. Genet Med. 2021. Epub ahead of print.

TARS1

  1. Theil AF, Botta E, Raams A, et al. Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype. Am J Hum Genet. 2019;105(2):434-440.

VARS1

  1. Karaca E, Harel T, Pehlivan D, et al. Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Neuron. 2015;88(3):499-513.
  2. Stephen J, Nampoothiri S, Banerjee A, et al. Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy. Hum Genet. 2018;137(4):293-303.
  3. Friedman J, Smith DE, Issa MY, et al. Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy. Nat Commun. 2019;10(1):707.

YARS1

  1. Nowaczyk MJM, Huang L, Tarnopolsky M, et al. A novel multisystem disease associated with recessive mutations in the tyrosyl-tRNA synthetase (YARS) gene. Am J Med Genet Part A. 2017;173(1):126-134.
  2. Williams KB, Brigatti KW, Puffenberger EG, et al. Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease. Hum Mol Genet. 2019;28(4):525-538.
  3. Zeiad RKHM, Ferren EC, Young DD, et al. A Novel Homozygous Missense Mutation in the YARS Gene: Expanding the Phenotype of YARS Multisystem Disease . J Endocr Soc. 2021;5(2).