Two novel mutations (E86A, R113W) in argininosuccinate lyase deficiency and evidence for highly variable splicing of the human argininosuccinate lyase gene

Linnebank, Michael; Homberger, Anja; Rapp, B.; Winter, Christa L Tanganyika-de; Marquardt, Thorsten; Harms, Erik; Koch, Hans Georg

doi:10.1023/a:1005690005439

Cited by 22 publications

(8 citation statements)

References 9 publications

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“…to either its post-transcriptional or post-translational processing. The human ASL gene product has been shown previously to undergo highly variable splicing (42). The nature of the alteration here to the mouse ASL gene product is currently under investigation.…”

Section: Discussionmentioning

confidence: 90%

Analysis of the Cytosolic Proteome in a Cell Culture Model of Familial Amyotrophic Lateral Sclerosis Reveals Alterations to the Proteasome, Antioxidant Defenses, and Nitric Oxide Synthetic Pathways

Allen

Heath

Kirby

et al. 2003

Journal of Biological Chemistry

111

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Section: Discussionmentioning

confidence: 90%

Analysis of the Cytosolic Proteome in a Cell Culture Model of Familial Amyotrophic Lateral Sclerosis Reveals Alterations to the Proteasome, Antioxidant Defenses, and Nitric Oxide Synthetic Pathways

Allen

Heath

Kirby

et al. 2003

Journal of Biological Chemistry

111

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“…However, we cannot estimate to what extent our data depend on our study population. Due to the limitations of any association study, these results must be re-tested in independent study samples, especially since the frequency of the TT genotype of MTHFR c.677C>T in the control group was lower than expected (11)(12)(13). Also, the association of MTHFR c.677C>T with bulbar ALS only, which was observed in secondary explorative subgroup analyses, and the association of DHFR c.594+59del19bp with bulbar ALS should be re-tested.…”

Section: Discussionmentioning

confidence: 99%

The thermolabile variant of 5,10-methylenetetrahydrofolate reductase is a possible risk factor for amyotrophic lateral sclerosis

Kühnlein

Jung

Farkas

et al. 2010

Amyotrophic Lateral Sclerosis

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Hyperhomocysteinemia is a risk factor for neurodegeneration, and binding of copper by homocysteine is a putative underlying mechanism. As mutations of the copper-dependent superoxide dismutase are observed in familial ALS, we tested whether genetic variants with influence on homocysteine metabolism are associated with ALS. We compared the frequency of seven variants of genes involved in homocysteine metabolism in 162 patients with sporadic ALS and 162 controls who did not significantly differ in age (t = 1.27, p = 0.205) and gender (χ(2) = 2.48, p = 0.115) using binary regression analysis. Results showed that the variant MTHFR c.677C>T was significantly associated with ALS, i.e. the T-allele was more frequent among patients. Explorative regression analysis revealed that MTHFR c.677C>T was not associated with spinal ALS, but with bulbar onset: CC/CT/TT in patients 0.33/0.51/0.16 versus 0.50/0.44/0.06 in controls; Wald = 5.73, p = 0.017. In addition, DHFR c.594+59del19bp was not associated with spinal, but with bulbar onset: del,del/del,ins/ins,ins in patients 0.16/0.67/0.18 versus 0.11/0.52/0.37 in controls; Wald = 5.02, p = 0.025. The other variants did not show significant associations. In summary, the variants MTHFR c.677C>T and DHFR c.594+59del19bp are involved in homocysteine metabolism. Homocysteine is neurotoxic and binds copper. Thus, the individual variability of homocysteine metabolism, e.g. due to genetic variants, may contribute to the vulnerability of ALS.

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“…Thus, homozygous or heterozygosis variants in different regions are responsible for the reduced ASL activity in ASDL patients. Linnebank et al showed compound heterozygosity, with 257A>C in exon 3 and 337C>T in exon 4, in the ASL gene in patients with neonatal onset ASLD [25]. In this study, we identified compound heterozygous mutation in ASL in a Chinese patient with the late onset form of ASLD.…”

Section: Discussionmentioning

confidence: 57%

Whole-Exome Sequencing Identified a Novel Compound Heterozygous Genotype in ASL in a Chinese Han Patient with Argininosuccinate Lyase Deficiency

Zhao

Hou

Teng

et al. 2019

BioMed Research International

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Pathogenic variants in the argininosuccinate lyase (ASL) gene have been shown to cause argininosuccinate lyase deficiency (ASLD); therefore, sequencing analysis offers advantages for prenatal testing and counseling in families afflicted with this condition. Here, we performed a genetic analysis of an ASLD patient and his family with an aim to offer available information for clinical diagnosis. The research subjects were a 23-month-old patient with a high plasma level of citrulline and his unaffected parents. Whole-exome sequencing identified potential related ASL gene mutations in this trio. Enzymatic activity was detected spectrophotometrically by a coupled assay using arginase and measuring urea production. We identified a novel nonsynonymous mutation (c.206A>G, p.Lys69Arg) and a stop mutation (c.637C>T, p.Arg213∗) in ASL in a Chinese Han patient with ASLD. The enzymatic activity of a p.Lys69Arg ASL construct in human embryonic kidney 293T cells was significantly reduced compared to that of the wild-type construct, and no significant activity was observed for the p.Arg213∗ construct. Compound heterozygous p.Lys69Arg and p.Arg213∗ mutations that resulted in reduced ASL enzyme activity were found in a patient with ASLD. This finding expands the clinical spectrum of ASL pathogenic variants.

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Two novel mutations (E86A, R113W) in argininosuccinate lyase deficiency and evidence for highly variable splicing of the human argininosuccinate lyase gene

Cited by 22 publications

References 9 publications

Analysis of the Cytosolic Proteome in a Cell Culture Model of Familial Amyotrophic Lateral Sclerosis Reveals Alterations to the Proteasome, Antioxidant Defenses, and Nitric Oxide Synthetic Pathways

Analysis of the Cytosolic Proteome in a Cell Culture Model of Familial Amyotrophic Lateral Sclerosis Reveals Alterations to the Proteasome, Antioxidant Defenses, and Nitric Oxide Synthetic Pathways

The thermolabile variant of 5,10-methylenetetrahydrofolate reductase is a possible risk factor for amyotrophic lateral sclerosis

Whole-Exome Sequencing Identified a Novel Compound Heterozygous Genotype in ASL in a Chinese Han Patient with Argininosuccinate Lyase Deficiency

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