Sialuria via the GNE Gene, Exon 5

Sialuria is an autosomal dominant inborn error of metabolism characterized by accumulation and excretion of free sialic acid and normal or increased levels of neuraminidase activity (Seppala et al. 1999. PubMed ID: 10330343; Leroy et al. 2001. PubMed ID: 11326336; Champaigne et al. 2016. PubMed ID: 27142465). The mechanism for excessive sialic acid synthesis is failure of feed-back inhibition of UDP-N-acetylglucosamine 2-epimerase by the pathway’s end product N-acetylneuraminic acid (Thomas et al. 1989. PubMed ID: 2553307; Seppala et al. 1999. PubMed ID: 10330343). Fewer than 10 patients with Sialuria have been reported in the literature. Among these patients, clinical features, including hepatosplenomegaly, mildly coarse facies, mild motor delay, and massive urinary excretion of free N-acetylneuraminic acid, have presented in the first few months of life (Seppala et al. 1999. PubMed ID: 10330343; Leroy et al. 2001. PubMed ID: 11326336; Champaigne et al. 2016. PubMed ID: 27142465). The patients in these reports had near normal growth and development, unlike patients with lysosomal storage of N-acetylneuraminic acid. This preservation of growth and development in Sialuria patients is thought to occur because the accumulated N-acetylneuraminic acid is mostly restricted to the cytosolic fraction (Seppala et al. 1999. PubMed ID: 10330343).

Sialuria is an autosomal dominant inborn error of metabolism characterized by overproduction of cytosolic sialic acid. The disorder occurs as a result of mono-allelic pathogenic variants in the GNE gene, which encodes the bi-functional enzyme UDP-N-acetylglucosamine 2-epimerase. GNE is comprised of exons 1-12 (mRNA variant 1, NM_001128227), and is located on chromosome 9p12 (Celeste et al. 2014. PubMed ID: 24796702; Yardeni et al. 2011. PubMed ID: 21910480). GNE pathogenic variants associated with Sialuria are restricted to codons 294-297 (based on protein accession NP_001121699) and are believed to cause inactivation of the negative inhibitory domain of UDP-N-acetylglucosamine 2-epimerase leading to toxic overproduction of N-acetylneuraminic acid (Seppala et al. 1999. PubMed ID: 10330343). GNE Myopathy is an autosomal recessive allelic disorder.

Although few Sialuria patients have been reported in the literature, thus far all reported patients have had pathogenic variants in codons 294-297 in the GNE gene, which predicts the location of an allosteric regulatory site (Seppala et al. 1999. PubMed ID: 10330343; Leroy et al. 2001. PubMed ID: 11326336; Champaigne et al. 2016. PubMed ID: 27142465).

Testing for Sialuria involves bidirectional Sanger sequencing of exon 5 plus ~10 bp of flanking DNA on each side. Exon 5 of GNE contains codons 294-297 (NP_001121699) that define the allosteric site of GNE and which are mutated in all reported Sialuria subjects to date. We will also sequence this region in family members of patients known pathogenic variants, or to confirm research results.