Biochemical and molecular analyses of infantile free sialic acid storage disease in North American children

Kleta, Robert; Aughton, David J.; Rivkin, Michael J.; Huizing, Marjan; Strovel, Erin T.; Anikster, Yair; Orvisky, Eduard; Natowicz, Marvin R.; Krasnewich, Donna M.; Gahl, William A.

doi:10.1002/ajmg.a.20024

Cited by 33 publications

(21 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Another genetic disorder involves a defect in transport of sialic acids from lysosomes into the cytosol. A severe form of this defect is infantile sialic acid storage disease [58,59], and the milder version is called Salla disease [60]. Finally, ‘sialidoses’ are defects in the sialidase that removes sialic acids from glycoconjugates, resulting in accumulation of sialic-acid-containing macromolecules in the lysosome [61].…”

Section: Geneticsmentioning

confidence: 99%

Sialic acids in human health and disease

Varki

2008

Trends in Molecular Medicine

865

813

View full text Add to dashboard Cite

The surfaces of all vertebrate cells are decorated with a dense and complex array of sugar chains, which are mostly attached to proteins and lipids. Most soluble secreted proteins are also similarly decorated with such glycans. Sialic acids are a diverse family of sugar units with a nine-carbon backbone that are typically found attached to the outermost ends of these chains. Given their location and ubiquitous distribution, sialic acids can mediate or modulate a wide variety of physiological and pathological processes. This review considers some examples of their established and newly emerging roles in aspects of human physiology and disease.

show abstract

Section: Geneticsmentioning

confidence: 99%

Sialic acids in human health and disease

Varki

2008

Trends in Molecular Medicine

865

813

View full text Add to dashboard Cite

show abstract

“…Antibody binding was detected with FITC-goat anti-chicken IgY and Cascade Blue-goat anti-mouse IgG. (22,62). As shown in Fig.…”

Section: The Lysosomal Sialic Acid Transporter Is Required For Exportmentioning

confidence: 99%

Mechanism of Uptake and Incorporation of the Non-human Sialic Acid N-Glycolylneuraminic Acid into Human Cells*

Bardor¹,

Nguyen

Díaz

et al. 2005

Journal of Biological Chemistry

346

321

View full text Add to dashboard Cite

N-Glycolylneuraminic acid (Neu5Gc) is a widely expressed sialic acid in mammalian cells. Although humans are genetically deficient in producing Neu5Gc, small amounts are present in human cells in vivo. A dietary origin was suggested by human volunteer studies and by observing that free Neu5Gc is metabolically incorporated into cultured human carcinoma cells by unknown mechanisms. We now show that free Neu5Gc uptake also occurs in other human and mammalian cells. Inhibitors of certain non-clathrin-mediated endocytic pathways reduce Neu5Gc accumulation. Studies with human mutant cells show that the lysosomal sialic acid transporter is required for metabolic incorporation of free Neu5Gc. Incorporation of glycosidically bound Neu5Gc from exogenous glycoconjugates (relevant to human gut epithelial exposure to dietary Neu5Gc) requires the transporter as well as the lysosomal sialidase, which presumably acts to release free Neu5Gc. Thus, exogenous Neu5Gc reaches lysosomes via pinocytic/endocytic pathways and is exported in free form into the cytosol, becoming available for activation and transfer to glycoconjugates. In contrast, N-glycolylmannosamine (ManNGc) apparently traverses the plasma membrane by passive diffusion and becomes available for conversion to Neu5Gc in the cytosol. This mechanism can also explain the metabolic incorporation of chemically synthesized unnatural sialic acids, as reported by others. Finally, to our knowledge, this is the first example of delivery to the cytosol of an extracellular small molecule that cannot cross the plasma membrane, utilizing fluid pinocytosis and a specific lysosomal transporter. The approach could, thus, potentially be generalized to any small molecule that has a specific lysosomal transporter but not a plasma membrane transporter.Sialic acid (Sia) 1 is a generic name for a family of acidic nine carbon sugars typically found as the outermost units of glycan chains on the vertebrate cellular glycocalyx and on secreted glycoproteins (1, 2). Their location and widespread occurrence on all vertebrate cells allow them to be involved in processes such as pathogen binding, inflammation, immune response, and tumor metastasis (3-8).There are more than 50 kinds of Sias known in nature (2, 9, 10). Most are derived via biosynthetic modification of a Sia called N-acetylneuraminic acid (Neu5Ac) (3,4,9). The addition of a single oxygen atom to the N-acetyl group of Neu5Ac gives a very common variation called N-glycolylneuraminic acid (Neu5Gc). The surfaces of most primate cell types studied to date are dominated by two major Sias, which are Neu5Ac and Neu5Gc (11,12).For a Sia molecule to get attached to glycoconjugates it must first be activated by conversion to the sugar nucleotide derivative cytidine monophosphate-Sia (CMP-Sia). Thus, Sias are converted to CMP-Sias in the nucleus, which then return to the cytosol to be transported into the Golgi apparatus, where they serve as high energy donors for attaching Sias to newly synthesized glycoconjugates on their way to the cell surfac...

show abstract

“…ISSD has no geographic predominance. Most patients have been reported in Europe, but we recently described the genetic and clinical Wndings of a North American ISSD patient [11]. A large number of diVerent SLC17A5 mutations have been found in ISSD patients.…”

Section: Discussionmentioning

confidence: 98%

“…Mutation analysis was performed as described [11]. In short, genomic DNA was extracted from cultured Wbroblasts using a Wizard Genomic DNA PuriWcation Kit (Promega, Madison, WI, USA).…”

Section: Slc17a5 Mutation Analysismentioning

confidence: 99%

“…cDNA was synthesized by reverse transcription using 5 g of total RNA and a SuperScript First-Strand Synthesis System for RT-PCR, according to the manufacturer's protocol (Gibco-BRL, Grand Island, NY). AmpliWcation of the SLC17A5 gene was performed using 200-400 ng of cDNA, Ready-To-Go PCR Beads (Amersham-Pharmacia Biotech, Piscataway, NJ), and 10 pmol of each primer in a total volume of 25 L. The PCR conditions were as published [11]. Electrophoresis of the products was performed using 1% agarose.…”

Section: Slc17a5 Mutation Analysismentioning

confidence: 99%

See 1 more Smart Citation

Clinical, biochemical, and molecular diagnosis of a free sialic acid storage disease patient of moderate severity

Kleta¹,

Morse²,

Orvisky³

et al. 2004

Molecular Genetics and Metabolism

Self Cite

View full text Add to dashboard Cite

The allelic autosomal recessive lysosomal storage disorders Salla disease and infantile free sialic acid storage disease (ISSD) result from mutations in SLC17A5. This gene codes for sialin, a lysosomal membrane protein that transports the charged sugar, N-acetylneuraminic acid (sialic acid), out of lysosomes. ISSD has a severe phenotype with infantile onset, while the Finnish variant, Salla disease, has a milder phenotype with later onset. Both disorders cause developmental delay, and ISSD is generally fatal in early childhood. We describe a 30-month old non-Finnish, Caucasian child with global developmental delay of postnatal onset, language, and motor skills stagnant at a 3-4 month level, hypotonia, and mild but progressive coarsening of facial features. Urinary excretion of free sialic acid was elevated 4.5 times above control. EM of a skin biopsy revealed enlarged secondary lysosomes consistent with oligosaccharide storage. Free sialic acid in Wbroblasts was 3.8 § 0.9 nmol/mg protein (concurrent normal controls, 0.5 § 0.1); diVerential centrifugation indicated a lysosomal location. Genomic analysis revealed compound heterozygosity for two new SLC17A5 mutations. This child's clinical manifestations of a lysosomal free sialic acid storage disease are consistent with her sialin mutations and biochemical Wndings. The diVerential diagnosis of postnatal developmental delay should include free sialic acid storage disorders such as ISSD and Salla disease. Published by Elsevier Inc.

show abstract

Biochemical and molecular analyses of infantile free sialic acid storage disease in North American children

Cited by 33 publications

References 25 publications

Sialic acids in human health and disease

Sialic acids in human health and disease

Mechanism of Uptake and Incorporation of the Non-human Sialic Acid N-Glycolylneuraminic Acid into Human Cells*

Clinical, biochemical, and molecular diagnosis of a free sialic acid storage disease patient of moderate severity

Contact Info

Product

Resources

About