Alternative titles; symbols
HGNC Approved Gene Symbol: NARS1
Cytogenetic location: 18q21.31 Genomic coordinates (GRCh38): 18:57,600,656-57,621,836 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q21.31 | Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive | 619091 | Autosomal recessive | 3 |
| Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant | 619092 | Autosomal dominant | 3 |
The NARS1 gene encodes the cytoplasmic asparaginyl-tRNA synthetase that mediates the charging of the Asn amino acid onto its cognate transfer RNA, which is essential for protein synthesis (summary by Wang et al., 2020).
Cirullo et al. (1983) isolated hybrids between human peripheral leukocytes and a temperature-sensitive CHO cell line with a thermolabile asparaginyl-tRNA synthetase (EC 6.1.1.22), which they symbolized 'asnS.' Hybrids selected at 39 degrees C required the presence of human chromosome 18. Temperature-resistant hybrid cells contained 2 forms of ASNRS: 1 highly thermal resistant, like the human enzyme, and 1 highly thermolabile, like the CHO mutant enzyme.
Beaulande et al. (1998) cloned a human cytosolic ASNRS cDNA from a liver cDNA library. The deduced 548-amino acid protein has a predicted molecular mass of 62.9 kD and shares 53% sequence identity with the S. cerevisiae homolog.
Lo et al. (2014) reported the discovery of a large number of natural catalytic nulls for each human aminoacyl tRNA synthetase. Splicing events retain noncatalytic domains while ablating the catalytic domain to create catalytic nulls with diverse functions. Each synthetase is converted into several new signaling proteins with biologic activities 'orthogonal' to that of the catalytic parent. The recombinant aminoacyl tRNA synthetase variants had specific biologic activities across a spectrum of cell-based assays: about 46% across all species affect transcriptional regulation, 22% cell differentiation, 10% immunomodulation, 10% cytoprotection, and 4% each for proliferation, adipogenesis/cholesterol transport, and inflammatory response. Lo et al. (2014) identified in-frame splice variants of cytoplasmic aminoacyl tRNA synthetases. They identified 1 catalytic-null splice variant for AsnRS.
Using a DNA probe in human-rodent hybrid cells, Shows (1983) found that asparaginyl-tRNA synthetase segregated with peptidase A, a chromosome 18 marker.
By Western blot analysis, Beaulande et al. (1998) showed that a human autoimmune serum (anti-KS) neutralized human AsnRSc activity, suggesting that it is a class II aminoacyl-tRNA synthetase involved in autoimmune reactions.
Neurodevelopmental Disorder with Microcephaly, Impaired Language, and Gait Abnormalities
In 23 patients from 13 unrelated families with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; 619091), Wang et al. (2020) and Manole et al. (2020) identified homozygous or compound heterozygous mutations in the NARS1 gene (see, e.g., 108410.0001-108410.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Most of the mutations were missense, although 2 families carried a nonsense or frameshift mutation on 1 allele. Affected members of 7 consanguineous families (families 9-15) carried the same homozygous R545C mutation (108410.0004). Fibroblasts derived from 3 unrelated patients showed variably decreased NARS1 protein levels, impaired homodimerization, reduced cytoplasmic transferase activity, and decreased global protein synthesis compared to controls. These findings suggested that the mutations resulted in a loss of function. Induced neuronal progenitor cells derived from 2 unrelated patients were used to generate cultures of 3D cortical brain organoids (CO). Mutant organoids became progressively smaller with decreased diameter compared to controls beginning around division 52, modeling the microcephaly observed in the patients. Patient CO showed reduced generation of radial glial cells with abnormal neural rosette structure, depletion of rosettes and postmitotic neurons, and decreased proliferation and viability of progenitor cells compared to wildtype. RNA-seq analysis of patient cells detected abnormalities in cell cycle control and neuronal progenitor cell fate differentiation, suggesting a role for NARS1 in these processes.
Neurodevelopmental Disorder with Microcephaly, Impaired Language, Epilepsy, and Gait Abnormalities
In 6 unrelated patients (patients 1-6) with neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG; 619092), Manole et al. (2020) identified a de novo heterozygous nonsense mutation in the NARS1 gene (R534X; 108410.0006). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Cells derived from 1 patient showed a dramatic decrease in enzyme activity compared to wildtype. Expression of this mutation in zebrafish caused cyclopia and gastrulation defects. The authors postulated a toxic gain-of-function dominant-negative effect. Two additional patients (patients 7 and 8) with a similar disorder but without microcephaly carried de novo heterozygous missense variants in the NARS1 gene (G509S and R322L) that were not present in the gnomAD database. Functional studies of these variants were not performed.
In an 8-year-old girl, born of consanguineous parents from Libya (family MIC-1433, family 17), with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; 619091), Wang et al. (2020) and Manole et al. (2020) identified a homozygous c.50C-T transition (c.50C-T, NM_004539.4) in the NARS1 gene, resulting in a thr17-to-met (T17M) substitution at a conserved residue in the UNE-N domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was present in heterozygous state in 4 individuals in the gnomAD database. Patient-derived cells showed decreased NARS1 protein expression, decreased homodimer formation, reduced aminoacylation activity, and impaired global protein synthesis compared to controls, consistent with a loss of function. Family history revealed 2 similarly affected sibs who died in childhood.
In 2 sibs, born of unrelated Turkish parents (family MIC-2116, family 19), with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; 619091), Wang et al. (2020) and Manole et al. (2020) identified compound heterozygous mutations in the NARS1 gene: a 1-bp duplication (c.203dupA, NM_004539.4), resulting in a frameshift and premature termination (Met69AspfsTer4) in the N-terminal region, and a c.1067A-C transversion, resulting in an asp356-to-ala (D356A; 108410.0003) substitution at a conserved residue in the catalytic domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The frameshift was not found in the gnomAD database, whereas D356A was found in heterozygous state in 264 individuals. Cells derived from 1 patient showed decreased NARS1 protein expression, decreased homodimer formation, reduced aminoacylation activity, and impaired protein synthesis compared to controls, consistent with a loss of function.
For discussion of the c.1067A-C transversion (c.1067A-C, NM_004539.4) in the NARS1 gene, resulting in an asp356-to-ala (D356A) substitution, that was found in compound heterozygous state in 2 sibs with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; 619091) by Wang et al. (2020) and Manole et al. (2020), see 108410.0002.
In 15 patients from 7 unrelated families (families 9-15) with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; 619091), Wang et al. (2020) and Manole et al. (2020) identified a homozygous c.1633C-T transition (c.1633C-T, NM_004539.4) in the NARS1 gene, resulting in an arg545-to-cys (R545C) substitution at a conserved residue in the catalytic domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The variant was present in 5 heterozygotes in the gnomAD database. Western blot analysis of cells derived from 2 patients showed near normal protein levels, but functional studies demonstrated that the mutation resulted in reduced aminoacylation activity to about 40% of control values, consistent with a loss of function.
In 2 sibs from Kosovo (family 16) with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; 619091), Manole et al. (2020) identified a homozygous c.32G-C transversion (c.32G-C, NM_004539.4) in the NARS1 gene, resulting in an arg11-to-pro (R11P) substitution at the 5-prime end of the noncanonical UNE-N domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was found once in heterozygous state in the gnomAD database. Patient cells showed decreased NARS1 protein levels and a mild decrease in enzymatic activity (80% of controls). The authors suggested that this domain may have nontranslational functions that contribute to the phenotype. The patients had a severe form of the disorder with early-onset seizures and cerebral atrophy and delayed myelination on brain imaging.
In 6 unrelated patients (patients 1-6) with neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG; 619092), Manole et al. (2020) identified a de novo heterozygous c.1600C-T transition (c.1600C-T, NM_004539.4) in the NARS1 gene, resulting in an arg534-to-ter (R534X) substitution in the C terminus at a conserved residue 15 amino acids from the end of the protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Cells derived from 1 patient showed a dramatic decrease in enzyme activity compared to wildtype. Expression of this mutation in zebrafish caused cyclopia and gastrulation defects. The authors postulated a toxic gain-of-function dominant-negative effect.
Beaulande, M., Tarbouriech, N., Hartlein, M. Human cytosolic asparaginyl-tRNA synthetase: cDNA sequence, functional expression in Escherichia coli and characterization as human autoantigen. Nucleic Acids Res. 26: 521-524, 1998. [PubMed: 9421509] [Full Text: https://doi.org/10.1093/nar/26.2.521]
Cirullo, R. E., Arredondo-Vega, F. X., Smith, M., Wasmuth, J. J. Isolation and characterization of interspecific heat-resistant hybrids between a temperature-sensitive Chinese hamster cell asparaginyl-tRNA synthetase mutant and normal human leukocytes: assignment of human asnS gene to chromosome 18. Somat. Cell Genet. 9: 215-233, 1983. [PubMed: 6836455] [Full Text: https://doi.org/10.1007/BF01543178]
Lo, W.-S., Gardiner, E., Xu, Z., Lau, C.-F., Wang, F., Zhou, J. J., Mendlein, J. D., Nangle, L. A., Chiang, K. P., Yang, X.-L., Au, K.-F., Wong, W. H., Guo, M., Zhang, M., Schimmel, P. Human tRNA synthetase catalytic nulls with diverse functions. Science 345: 328-332, 2014. [PubMed: 25035493] [Full Text: https://doi.org/10.1126/science.1252943]
Manole, A., Efthymiou, S., O'Connor, E., Mendes, M. I., Jennings, M., Maroofian, R., Davagnanam, I., Mankad, K., Lopez, M. R., Salpietro, V., Harripaul, R., Badalato, L., and 81 others. 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. 107: 311-324, 2020. [PubMed: 32738225] [Full Text: https://doi.org/10.1016/j.ajhg.2020.06.016]
Shows, T. B. Personal Communication. Buffalo, N. Y. 1/11/1983.
Wang, L., Li, Z., Sievert, D., Smith, D. E. C., Mendes, M. I., Chen, D. Y., Stanley, V., Ghosh, S., Wang, Y., Kara, M., Aslanger, A. D., Rosti, R. O., Houlden, H., Salomons, G. S., Gleeson, J. G. Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly. Nature Commun. 11: 4038, 2020. Note: Electronic Article. Erratum: Nature Commun. 12: 1192, 2021. Electronic Article. [PubMed: 32788587] [Full Text: https://doi.org/10.1038/s41467-020-17454-4]