Asparagine Synthetase Deficiency causes reduced proliferation of cells under conditions of limited asparagine

Palmer, Elizabeth E.; Hayner, Jaclyn N.; Sachdev, Rani; Cardamone, Michael; Kandula, Tejaswi; Morris, Paula; Dias, Kerith-Rae; Jiang, Tao; Miller, David F.; Zhu, Ying; Macintosh, Rebecca; Dinger, Marcel E.; Cowley, Mark J.; Buckley, Michael F.; Roscioli, Tony; Bye, Ann; Kilberg, Michael S.; Kirk, Edwin P.

doi:10.1016/j.ymgme.2015.08.007

Cited by 51 publications

(79 citation statements)

References 27 publications

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“…Consistent with this hypothesis, the cerebrospinal fluid levels of asparagine, as with many amino acids, are only a fraction of those in the plasma (34,35). Consequently, a decrease in ASNS catalytic activity in the brain is presumed to cause the disease phenotype (23,24,26). Plasma asparagine levels were reduced in 8 out of 16 ASD patients for whom plasma analysis was reported (reviewed in Ref.…”

Section: Asparagine Synthetase Deficiencymentioning

confidence: 89%

“…Symptoms include intellectual disability, microcephaly, severe developmental delay, intractable seizures, progressive brain atrophy, and more rarely, respiratory deficiency (23)(24)(25)(26)(27)(28)(29)(30). The disease is associated with homozygous or compound heterozygous mutations within the ASNS gene on chromosome 7q2, but the exact mechanisms that cause the overt symptoms of the disease are not well understood (23,26,31). The fact that the children are born with epileptic-like seizures and microcephaly suggests that brain ASNS activity is critical for development of this organ.…”

Section: Asparagine Synthetase Deficiencymentioning

confidence: 99%

“…However, cerebrospinal fluid asparagine content has been analyzed in only four ASD patients, and it was undetectable in two of the four (24,27,30). Recent studies with ASD patients' fibroblasts have revealed that lowering the asparagine concentration in the extracellular milieu results in an inability to proliferate (26). These cell culture studies also showed that fibroblasts from asymptomatic heterozygote parents exhibit no ill effects in the presence of sufficient extracellular asparagine, but decline in proliferative capacity when placed in an asparagine-free medium.…”

Section: Asparagine Synthetase Deficiencymentioning

confidence: 99%

“…Cell culture analyses have shown that several of the aforementioned mutations do not affect mRNA stability (23,26). Rather, many of the disease-associated mutations are expected to decrease enzyme activity and/or protein stability.…”

Section: Structural Examination Of Asd Mutationsmentioning

confidence: 99%

“…The C-terminal domain mutations G289A and T337I are associated with an afflicted child who is a compound heterozygote. Both mutations are located proximal to the ATP-binding pocket (26). The G289A mutation results in a steric clash with Ser 293 , whereas the T337I mutation introduces a hydrophobic patch on the protein surface that may decrease solubility.…”

Section: Minireview: Asparagine Synthetase: Role In Diseasementioning

confidence: 99%

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Asparagine synthetase: Function, structure, and role in disease

Lomelino¹,

Andring²,

McKenna³

et al. 2017

Journal of Biological Chemistry

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237

203

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Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. Elevated ASNS protein expression is associated with resistance to asparaginase therapy in childhood acute lymphoblastic leukemia. There is evidence that ASNS expression levels may also be inversely correlated with asparaginase efficacy in certain solid tumors as well. Children with mutations in the ASNS gene exhibit developmental delays, intellectual disability, microcephaly, intractable seizures, and progressive brain atrophy. Thus far, 15 unique mutations in the ASNS gene have been clinically associated with asparagine synthetase deficiency (ASD). Molecular modeling using the Escherichia coli ASNS-B structure has revealed that most of the reported ASD substitutions are located near catalytic sites or within highly conserved regions of the protein. For some ASD patients, fibroblast cell culture studies have eliminated protein and mRNA synthesis or stability as the basis for decreased proliferation.

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Section: Asparagine Synthetase Deficiencymentioning

confidence: 89%

Section: Asparagine Synthetase Deficiencymentioning

confidence: 99%

Section: Asparagine Synthetase Deficiencymentioning

confidence: 99%

Section: Structural Examination Of Asd Mutationsmentioning

confidence: 99%

Section: Minireview: Asparagine Synthetase: Role In Diseasementioning

confidence: 99%

See 3 more Smart Citations

Asparagine synthetase: Function, structure, and role in disease

Lomelino¹,

Andring²,

McKenna³

et al. 2017

Journal of Biological Chemistry

Self Cite

237

203

View full text Add to dashboard Cite

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Genetics of Epileptic Encephalopathies

Palmer

Sachdev

Macintosh

et al. 2017

Encyclopedia of Life Sciences

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Epileptic encephalopathy (EE) is a descriptive term for a group of severe epilepsy disorders characterised predominantly by early onset drug‐resistant seizures, accompanied by developmental stagnation or regression secondary to epileptiform activity. The aetiological diagnosis of EE is challenging, as causes are numerous with significant phenotypic overlap: these include acquired causes as well as numerous de novo or inherited monogenic seizure disorders, genetic inborn errors of metabolism, intellectual disability syndromes and chromosomal aberrations. A diagnostic pathway should include consultation with a Paediatric Neurologist and Clinical Geneticist, screening for immediately treatable causes, neuroimaging and electroencephalogram (EEG) and genetic testing including chromosomal microarray and consideration of a next generation sequencing technique that can interrogate multiple genetic causes, such as a multigene panel, or exome/genome sequencing. Understanding the underlying genetic cause of EE can allow accurate genetic counselling for the family and providing personalised management and support. Key Concepts EE is a descriptive term for a group of disorders where epileptiform activity itself contributes to severe cognitive and behavioural impairments above and beyond what might be expected from the underlying pathology. Although EE can be acquired, most cases of previously considered cryptogenic EE are now recognised to be due to single gene disorders. The majority of monogenic EE are due to de novo pathogenic variants: however, up to 10% of EE may be due to X‐linked or autosomal recessive conditions, with higher rates in populations where consanguineous marriage is more common. Although there are some genotype/phenotype correlations, a single genetic cause can result in a variety of EE and non‐EE phenotypes, and each subtype of EE can have a variety of genetic causes. Genetic heterogeneity in EE limits the value of targeted genetic testing. An optimal, cost‐effective diagnostic approach involves first‐tier tests that target common and treatable conditions, followed by second‐tier tests including sequencing of a panel of genes known to cause EE or exome/whole genome sequencing to allow genome‐wide interrogation. Factors influencing choice of type of genetic test (multigene panel versus exome/genome sequencing) include epilepsy semiology, developmental regression, additional neurological or extra‐cerebral manifestations, family history and clinician and patient choice and cost. Phenotypic factors that suggest exome/genome sequencing may be valuable and include developmental regression and progressive features, multiorgan involvement including dysmorphism, additional neurological features and cerebral malformations. Evaluation of the likely pathogenicity of a novel genetic variant should include consideration of similarity with the types of genetic variants previously identified as causal of EE for that gene, including which functional domain(s) are implicated as well as overlap with the associated clinical features previously described for that condition. For variants remaining of uncertain clinical significance, ongoing pathogenicity assessment will be required in the light of advances in the understanding of the genetics of EE.

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Rapid exome sequencing and adjunct RNA studies confirm the pathogenicity of a novel homozygous ASNS splicing variant in a critically ill neonate

et al. 2020

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Rapid genomic diagnosis programs are transforming rare disease diagnosis in acute pediatrics. A ventilated newborn with cerebellar hypoplasia underwent rapid exome sequencing (75 h), identifying a novel homozygous ASNS splice-site variant (NM_133436.3:c.1476+1G>A) of uncertain significance. Rapid ASNS splicing studies using blood-derived messenger RNA from the family trio confirmed a consistent pattern of abnormal splicing induced by the variant (cryptic 5′ splice-site or exon 12 skipping) with absence of normal ASNS splicing in the proband. Splicing studies reported within 10 days led to reclassification of c.1476+1G>A as pathogenic at age 27 days. Intensive care was redirected toward palliation. Cost analyses for the neonate and his undiagnosed, similarly affected deceased sibling, demonstrate that early diagnosis reduced hospitalization costs by AU$100,828. We highlight the diagnostic benefits of adjunct RNA testing to confirm the pathogenicity of splicing

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Asparagine Synthetase Deficiency causes reduced proliferation of cells under conditions of limited asparagine

Cited by 51 publications

References 27 publications

Asparagine synthetase: Function, structure, and role in disease

Asparagine synthetase: Function, structure, and role in disease

Genetics of Epileptic Encephalopathies

Rapid exome sequencing and adjunct RNA studies confirm the pathogenicity of a novel homozygous ASNS splicing variant in a critically ill neonate

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