Increased Polysialylation of the Neural Cell Adhesion Molecule in a Transgenic Mouse Model of Sialuria

Kreuzmann, Denise; Horstkorte, Rüdiger; Kohla, Guido; Kannicht, Christoph; Bennmann, Dorit; Thate, Annett; Bork, Kaya

doi:10.1002/cbic.201600580

Cited by 6 publications

(5 citation statements)

References 24 publications

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“…Three are associated with a decreased free Sia production: GNE myopathy (GNE mutations, Online Mendelian Inheritance in Man (OMIM) 605820), manifesting with the distal muscle weakness leading patients to a wheelchair-bound state (5); spondyloepimetaphyseal dysplasia, Genevieve type (NANS mutations, OMIM 610442), causing severe neurodevelopmental delay and skeletal dysplasia (6); and congenital disorder of glycosylation, type IIf (OMIM 603585), caused by cytidine monophosphate (CMP)-Sia transporter deficiency (SLC35A1 mutations) and presenting with proteinuria, macro-thrombocytopenia, and neurological disease (7)(8)(9). The remaining three, associated with increased levels of free Sia, are French-type sialuria (OMIM 269921, GNE mutations), leading to developmental delays (10), and infantile sialic storage/Salla disease (OMIM 269920/604369, SLC17A5 mutations), causing progressive neurologic deterioration and resulting in psychomotor delay, spasticity, athetosis, and epileptic seizures (11). No specific therapies for any of these diseases have been approved yet, highlighting the need of further research in this area (12).…”

Section: Introductionmentioning

confidence: 99%

N -acetylneuraminate pyruvate lyase controls sialylation of muscle glycoproteins essential for muscle regeneration and function

Da Silva,

Dort,

Orfi

et al. 2023

Sci. Adv.

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Deleterious variants in N- acetylneuraminate pyruvate lyase (NPL) cause skeletal myopathy and cardiac edema in humans and zebrafish, but its physiological role remains unknown. We report generation of mouse models of the disease: Npl R63C , carrying the human p.Arg63Cys variant, and Npl del116 with a 116-bp exonic deletion. In both strains, NPL deficiency causes drastic increase in free sialic acid levels, reduction of skeletal muscle force and endurance, slower healing and smaller size of newly formed myofibers after cardiotoxin-induced muscle injury, increased glycolysis, partially impaired mitochondrial function, and aberrant sialylation of dystroglycan and mitochondrial LRP130 protein. NPL-catalyzed degradation of sialic acid in the muscle increases after fasting and injury and in human patient and mouse models with genetic muscle dystrophy, demonstrating that NPL is essential for muscle function and regeneration and serves as a general marker of muscle damage. Oral administration of N- acetylmannosamine rescues skeletal myopathy, as well as mitochondrial and structural abnormalities in Npl R63C mice, suggesting a potential treatment for human patients.

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Section: Introductionmentioning

confidence: 99%

N -acetylneuraminate pyruvate lyase controls sialylation of muscle glycoproteins essential for muscle regeneration and function

Da Silva,

Dort,

Orfi

et al. 2023

Sci. Adv.

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“… 42 Increased activity of the bifunctional enzyme UDP- N -acetylglucosamine 2-epimerase/ N -acetylmannosamine kinase results in sialuria, an extremely rare genetic disorder, while knockout of the corresponding gene is lethal in mice. 43,44 Mutations in this epimerase are linked to hereditary inclusion body myopathy (HIBM). 44,45 In addition, O -ureidoserine racemase is involved in the biosynthesis of the antibiotic d -cycloserine, 46 while a peptide epimerase is found in funnel web spider ( Agelenopsis aperta ) venom which interconverts two 48 amino-acid peptides differing only in the configuration at a single serine residue (Ser-46).…”

Section: Introductionmentioning

confidence: 99%

Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition

et al. 2021

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“…Sialuria, an autosomal dominant disorder found in patients with a defective synthesis of a key enzyme UDP-N-acetylglucosamine-2-epimerase N-acetylmannosamine kinase (GNE) due to the mutation in the R263L region of the GNE gene. Due to this mutation, the negative feedback inhibition is lost, disrupting sialic acid synthesis in mammals 1 . In sialuria, an increased overproduction of free sialic acid is found in the cytosol.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to this, a significantly higher expression of sialylation was observed on the surface of leukocytes. Kreuzmann and colleagues (2017) proved that the developmental delays associated with sialuria patient are due to increased intracellular levels of sialic acid that causes polysialylation on NCAM 1 .…”

Section: Introductionmentioning

confidence: 99%

The Identification of Sialuria with Different Degrees of Intellectual Disabilities in Children and Adolescents

Ishtiaq

Siddiqui

Nawaz

et al. 2021

Ann. psychophysiol.

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Background: Single nucleotide polymorphism/mutation in the R263L region of the allosteric site of the GNE gene produces a phenotype with an overproduction of intracellular levels of sialic acid and causes sialuria. In sialuria, a defective GNE gene, synthesized with lost feedback inhibition mechanism, produces many developmental delays and varying degrees of intellectual disabilities in children and adolescents. Several mutations in the epimerase and kinase domains exist that cause difficulty in getting a precise and exact effect of the GNE gene on the disease severity and sialic acid levels. This is the first study investigating the molecular basis of neuronal disorders exhibiting sialuria in Pakistani children/ adolescents. Methodology: The current study quantified the mRNA expression of the GNE gene and urinary sialic acid concentration by Realtime-qRT-PCR and Fluorimetric assays, respectively. The correlation between relative mRNA and urinary sialic acid levels was evaluated by using Pearson Bivariate correlations. Results: The data show that severely intellectually disabled (I.D.) patients showed significantly reduced mRNA expression levels of the GNE gene compared to controls. The concentrations of free sialic acid in urine were significantly reduced in severe I.D. patients compared to controls. Whereas patients with mild I.D. showed a two-fold increase in sialic acid levels when compared to controls. A significant correlation was found between an increased GNE mRNA and low urinary sialic acid levels from severe I.D. patients. Conclusion: The effect of the GNE gene is beyond hyposialylation that could hinder N-glycan structure and sialic acid biosynthesis. The study highlighted the possible involvement of sialic acid levels with different degrees of intellectual disabilities in Pakistani children and adolescents.

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Increased Polysialylation of the Neural Cell Adhesion Molecule in a Transgenic Mouse Model of Sialuria

Abstract: DeniseK reuzmann, [a] RüdigerH orstkorte,* [a] GuidoK ohla, [b] Christoph Kannicht, [b] Dorit Bennmann, [a] AnnettT hate, [a] and Kaya Bork [a] This work is dedicated to Werner Reutter,apioneer in thebiosynthesis of sialic acids, who first purifiedand cloned GNE in 1997.

Cited by 6 publications

References 24 publications

N -acetylneuraminate pyruvate lyase controls sialylation of muscle glycoproteins essential for muscle regeneration and function

N -acetylneuraminate pyruvate lyase controls sialylation of muscle glycoproteins essential for muscle regeneration and function

Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition

The Identification of Sialuria with Different Degrees of Intellectual Disabilities in Children and Adolescents

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