Alternative titles; symbols
HGNC Approved Gene Symbol: ASNS
SNOMEDCT: 782757004;
Cytogenetic location: 7q21.3 Genomic coordinates (GRCh38) : 7:97,851,677-97,928,441 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q21.3 | Asparagine synthetase deficiency | 615574 | Autosomal recessive | 3 |
The ASNS gene encodes asparagine synthetase (EC 6.3.5.4), an enzyme that catalyzes the transfer of ammonia from glutamine to aspartic acid to form asparagine. It is expressed in most mammalian cells (summary by Zhang et al., 1989 and Ruzzo et al., 2013).
Greco et al. (1987) cloned human ASNS based on its ability to complement ts11, a temperature-sensitive (ts) mutant of the BHK hamster cell line that at the nonpermissive temperature is blocked in progression through the G1 phase of the cell growth cycle. The gene was transcribed into an mRNA of 2 kb that was expressed in all human, hamster, and mouse cell lines tested. It encodes a protein of about 550 amino acids.
Asns is highly expressed in the adult mouse brain. Ruzzo et al. (2013) found that Asns is also expressed in the developing embryonic mouse brain in the cortical plate and the ventricular and subventricular zones where neural progenitors reside.
Zhang et al. (1989) demonstrated that the ASNS gene spans 35 kb and contains 13 exons. The 5-prime upstream region of this gene, like other housekeeping genes, lacks conventional TATA and CAAT boxes. Both the human and the hamster genes have a high 5-prime G+C content which may play a role in expression through DNA methylation.
The gene for ASNS has been assigned to chromosome 7 by enzymatic analyses of human/hamster hybrids (Arfin et al., 1983). Lambert et al. (1986) confirmed this assignment with molecular probes. Using a genomic probe, Greco et al. (1989) found that the ts11 locus is derived from the long arm of human chromosome 7, proximal to the TCRB locus (see 186930). In situ hybridization mapped the locus more precisely to chromosome 7q21-q31. Two other members of the gene family detected by the ts11 probe were mapped to chromosomes 8pter-q24 and 21pter-q22.
Heng et al. (1994) refined the localization of the ASNS gene to chromosome 7q21.3 by fluorescence in situ hybridization.
Siu et al. (2002) presented evidence that ATF4 (604064) binds nutrient-sensing response element-1 (NSRE1) in the human ASNS gene and activates ASNS transcription in response to nutrient stress.
In 9 patients from 4 unrelated families with asparagine synthetase deficiency (ASNSD; 615574), Ruzzo et al. (2013) identified 3 different homozygous or compound heterozygous missense mutations in the ASNS gene (108370.0001-108370.0003). The mutations were found by whole-exome sequencing and segregated with the disorder in all families. The phenotype was characterized by microcephaly, severely delayed psychomotor development, progressive encephalopathy, and seizure or hyperekplexic activity. Brain imaging showed cortical atrophy, enlarged ventricles, and cortical dysplasia. Affected individuals had onset in utero or at birth, and 6 died in infancy. Functional studies were not performed, but cellular studies showed that 2 of the mutant proteins were expressed at lower levels compared to wildtype and the third mutant protein was expressed at higher levels than wildtype. Two patients had decreased levels of asparagine, whereas a third had increased levels of glutamine and aspartic acid. Ruzzo et al. (2013) postulated a loss-of-function effect. Ruzzo et al. (2013) suggested that the brain is responsible for local de novo synthesis of asparagine, which may explain why the phenotype was neurologically restricted. Brain accumulation of aspartate and glutamate may result in increased excitability, seizure activity, and neuronal damage.
In 2 sisters with ASNSD from a consanguineous Indian family, Sun et al. (2017) identified a homozygous missense mutation in the ASNS gene (R340H; 108370.0004). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
By whole-exome sequencing of an archived newborn blood spot, Abhyankar et al. (2018) identified compound heterozygous mutations in the ASNS gene (G366D, 108370.0005; V243A, 108370.0006). The infant, who died at 15 months of age without a specific diagnosis, had typical findings consistent with asparagine synthetase deficiency.
In a girl with ASNSD from a nonconsanguineous Indian family, Gupta et al. (2017) identified a homozygous missense mutation in the ASNS gene (A380S; 108370.0007). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
Sacharow et al. (2018) identified a homozygous mutation in the ASNS gene (R49Q; 108370.0008) in 2 sibs, born to consanguineous Emirati parents, with ASNSD. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family.
Ruzzo et al. (2013) found that homozygous mice with a hypomorphic Asns mutation (about 20% residual enzyme activity) had structural brain abnormalities, including reduced cortical thickness and enlarged ventricles. Mutant mice also showed deficits in learning and memory. Mutant mice did not show abnormal motor activity or seizure activity.
In affected members of 2 Iranian Jewish families with asparagine synthetase deficiency (ASNSD; 615574), Ruzzo et al. (2013) identified a homozygous c.1084T-G transversion in the ASNS gene, resulting in a phe362-to-val (F362V) substitution at a highly conserved residue. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not found in the dbSNP (build 135), 1000 Genomes Project, or Exome Sequencing Project databases or in 1,160 controls or 261 in-house exomes. It was found in 1 of 80 ancestry-matched controls, yielding a carrier frequency of 0.0125 in individuals of Iranian Jewish ancestry. Haplotype analysis indicated a founder effect. In vitro functional expression studies showed decreased amounts of mutant ASNS protein in HEK293 and COS-7 cells compared to wildtype. Glutamine and aspartic acid were increased in patients from 1 of the families. Ruzzo et al. (2013) postulated a loss-of-function effect.
In 3 male sibs, born of consanguineous Bangladeshi parents, with asparagine synthetase deficiency (ASNSD; 615574), Ruzzo et al. (2013) identified a homozygous c.1648C-T transition in the ASNS gene, resulting in an arg550-to-cys (R550C) substitution. Three male sibs from a French Canadian family with the disorder were found to be compound heterozygous for R550C and a c.17C-A transversion, resulting in an ala6-to-glu (A6E; 108370.0003) substitution. Both mutations occurred at highly conserved residues. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Neither mutation was found in the dbSNP (build 135), 1000 Genomes Project, or Exome Sequencing Project databases or in 1,160 controls, 169 in-house exomes, or 300 ancestry-matched controls. In vitro functional expression studies in HEK293 and COS-7 cells showed decreased amounts of mutant A6E protein compared to wildtype, whereas the mutant R550C protein was increased compared to wildtype. Asparagine levels were decreased in 1 patient from each family. Ruzzo et al. (2013) postulated a loss-of-function effect, either by decreased amounts of ASNS protein (A6E) or decreased function (R550C).
For discussion of the ala6-to-glu (A6E) mutation in the ASNS gene that was found in compound heterozygous state in sibs with asparagine synthetase deficiency (ASNSD; 615574) by Ruzzo et al. (2013), see 108370.0002.
In 2 sisters, born of consanguineous Indian parents, with asparagine synthetase deficiency (ASNSD; 615574) accompanied by diaphragmatic eventration, Sun et al. (2017) identified a homozygous c.1019G-A transition in the ASNS gene, resulting in an arg340-to-his (R340H) substitution at a highly conserved residue in the C-terminal domain of the enzyme. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The parents and unaffected sibs were heterozygous for the mutation. The mutation was not found in public or internal databases. The one sister who was tested had reduced plasma asparagine levels, providing support for the diagnosis.
By whole-exome sequencing of an archived newborn blood spot, Abhyankar et al. (2018) identified an infant with compound heterozygous mutations in the ASNS gene: a c.1097G-A transition (c.1097G-A, NM_001673.4), resulting in a gly366-to-glu (G366E) substitution, and a c.728T-C transition, resulting in a val243-to-ala (V243A) substitution (108370.0006). Both mutations occurred in the highly conserved asparagine synthetase domain. The mutations were confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations. The G366E variant was not present in the 1000 Genomes Project, ExAC, or UK10K databases; the V243A variant had a low minor allele frequency of 0.0002 and 0.000008 in the 1000 Genomes Project and ExAC databases, respectively, and was not seen in homozygosity.
For discussion of the c.728C-T transition (c.728C-T, NM_001673.4) in the ASNS gene, resulting in a val243-to-ala (V243A) substitution, that was found in compound heterozygous state in a patient with asparagine synthetase deficiency (ASNSD; 615574) by Abhyankar et al. (2018), see 108370.0005.
In a girl, born of nonconsanguineous Indian parents, with asparagine synthetase deficiency (ASNSD; 615574), Gupta et al. (2017) identified a homozygous c.1138G-T transversion (chr7.97,483,992C-A, GRCh37) in exon 11 of the ASNS gene, resulting in an ala380-to-ser (A380S) substitution in the C-terminal asparagine synthetase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant had a frequency of 0.000008313 in the ExAC database. Structural modeling suggested that the mutation affects the helix-turn-helix motif and ASNS function.
In 2 sibs, born to consanguineous Emirati parents, with asparagine synthetase deficiency (ASNSD; 615574), Sacharow et al. (2018) identified a homozygous c.146G-A transition (c.146G-A, NM_183356) in the ASNS gene, resulting in an arg49-to-gln (R49Q) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. The variant has a low frequency (7.21 x 10(-6)) in the gnomAD database. Structural modeling suggested that the mutation affects the glutamine binding pocket of the protein. Studies in fibroblasts from patients showed that little to no cellular growth compared to controls in asparagine-depleted cell media, and fibroblasts from heterozygous parents showed moderate cellular growth compared to controls. The R49G variant did not appear to affect ASNS synthesis or stability.
Abhyankar, A., Lamendola-Essel, M., Brennan, K., Giordano, J. L., Esteves, C., Felice, V., Wapner, R., Jobanputra, V. Clinical whole exome sequencing from dried blood spot identifies novel genetic defect underlying asparagine synthetase deficiency. Clin. Case Rep. 6: 200-205, 2018. [PubMed: 29375865] [Full Text: https://doi.org/10.1002/ccr3.1284]
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Greco, A., Ittmann, M., Basilico, C. Molecular cloning of a gene that is necessary for G(1) progression in mammalian cells. Proc. Nat. Acad. Sci. 84: 1565-1569, 1987. [PubMed: 3470743] [Full Text: https://doi.org/10.1073/pnas.84.6.1565]
Gupta, N., Tewari, V. V., Kumar, M., Langeh, N., Gupta, A., Mishra, P., Kaur, P., Langeh, N., Gupta, A., Mishra, P., Kaur, P., Ramprasad, V., Murugan, S., Kumar, R., Jana, M., Kabra, M. Asparagine synthetase deficiency--report of a novel mutation and review of the literature. Metab. Brain Dis. 32: 1889-1900, 2017. Note: Erratum: Metab. Brain Dis. 32: 1901 only, 2017. [PubMed: 28776279] [Full Text: https://doi.org/10.1007/s11011-017-0073-6]
Heng, H. H. Q., Shi, X.-M., Scherer, S. W., Andrulis, I. L., Tsui, L.-C. Refined localization of the asparagine synthetase gene (ASNS) to chromosome 7, region q21.3, and characterization of the somatic cell hybrid line 4AF/106/KO15. Cytogenet. Cell Genet. 66: 135-138, 1994. [PubMed: 7904551] [Full Text: https://doi.org/10.1159/000133685]
Lambert, M. A., Cairney, A. E. L., Ray, P. N., Weksberg, R., Andrulis, I. L. Genomic characterization of the human asparagine synthetase gene. (Abstract) Am. J. Hum. Genet. 39: A207 only, 1986.
Ruzzo, E. K., Capo-Chichi, J.-M., Ben-Zeev, B., Chitayat, D., Mao, H., Pappas, A. L., Hitomi, Y., Lu, Y.-F., Yao, X., Hamdan, F. F., Pelak, K., Reznik-Wolf, H., and 32 others. Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy. Neuron 80: 429-441, 2013. [PubMed: 24139043] [Full Text: https://doi.org/10.1016/j.neuron.2013.08.013]
Sacharow, S. J., Dudenhausen, E. E., Lomelino, C. L., Rodan, L., El Achkar, C. M., Olson, H. E., Genetti, C. A., Agrawal, P. B., McKenna, R., Kilberg, M. S. Characterization of a novel variant in siblings with asparagine synthetase deficiency. Molec. Genet. Metab. 123: 317-325, 2018. [PubMed: 29279279] [Full Text: https://doi.org/10.1016/j.ymgme.2017.12.433]
Siu, F., Bain, P. J., LeBlanc-Chaffin, R., Chen, H., Kilberg, M. S. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. J. Biol. Chem. 277: 24120-24127, 2002. [PubMed: 11960987] [Full Text: https://doi.org/10.1074/jbc.M201959200]
Sun, J., McGillivray, A. J., Pinner, J., Yan, Z., Liu, F., Bratkovic, D., Thompson, E., Wei, X., Jiang, H., Asan, Chopra, M. Diaphragmatic eventration in sisters with asparagine synthetase deficiency: a novel homozygous ASNS mutation and expanded phenotype. JIMD Rep. 34: 1-9, 2017. [PubMed: 27469131] [Full Text: https://doi.org/10.1007/8904_2016_3]
Zhang, Y. P., Lambert, M. A., Cairney, A. E. L., Wills, D., Ray, P. N., Andrulis, I. L. Molecular structure of the human asparagine synthetase gene. Genomics 4: 259-265, 1989. [PubMed: 2565875] [Full Text: https://doi.org/10.1016/0888-7543(89)90329-7]