Abstract
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.
Highlights
Sialuria, an autosomal dominant disorder found in patients with a defective synthesis of a key enzyme UDP-N-acetylglucosamine2-epimerase N-acetylmannosamine kinase (GNE) due to the mutation in the R263L region of the GNE gene
There was an ave rage two-fold increase in the urinary sialic acid levels in mild I.D. subjects compared to controls
Results from Reverse Transcriptase Minus (RT-)qPCR showed a significant reduction in the I.D. mRNA expression of the GNE gene in mild, moderate, and severe I.D. subjects
Summary
An autosomal dominant disorder found in patients with a defective synthesis of a key enzyme UDP-N-acetylglucosamine2-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]. 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. 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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