Background: Previously, we identified two missense mutations in the chondroitin N-acetylgalactosaminyltransferase-1 gene in patients with neuropathy. These mutations are associated with a profound decrease in chondroitin N-acetylgalactosaminyltransferase-1 enzyme activity. Here, we describe a patient with neuropathy who is heterozygous for a chondroitin synthase-1 mutation. Chondroitin synthase-1 has two glycosyltransferase activities: it acts as a GlcUA and a GalNAc transferase and is responsible for adding repeated disaccharide units to growing chondroitin sulfate chains.
Methods: Recombinant wild-type chondroitin synthase-1 enzyme and the F362S mutant were expressed. These enzymes and cells expressing them were then characterized.
Results: The mutant chondroitin synthase-1 protein retained approximately 50% of each glycosyltransferase activity relative to the wild-type chondroitin synthase-1 protein. Furthermore, unlike chondroitin polymerase comprised of wild-type chondroitin synthase-1 protein, the non-reducing terminal 4-O-sulfation of GalNAc residues synthesized by chondroitin N-acetylgalactosaminyltransferase-1 did not facilitate the elongation of chondroitin sulfate chains when chondroitin polymerase that consists of the mutant chondroitin synthase-1 protein was used as the enzyme source.
Conclusions: The chondroitin synthase-1 F362S mutation in a patient with neuropathy resulted in a decrease in chondroitin polymerization activity and the mutant protein was defective in regulating the number of chondroitin sulfate chains via chondroitin N-acetylgalactosaminyltransferase-1. Thus, the progression of peripheral neuropathies may result from defects in these regulatory systems.
General significance: The elongation of chondroitin sulfate chains may be tightly regulated by the cooperative expression of chondroitin synthase-1 and chondroitin N-acetylgalactosaminyltransferase-1 in peripheral neurons and peripheral neuropathies may result from synthesis of abnormally truncated chondroitin sulfate chains.
Keywords: CS; ChGn; ChPF; ChSy; Chondroitin sulfate; GalNAcT; GlcAT; Glycosaminoglycan; Glycosyltransferase; N-acetylgalactosaminyltransferase; Neuropathy; Proteoglycan; chondroitin GalNAcT; chondroitin polymerizing factor; chondroitin sulfate; chondroitin synthase; glucuronyltransferase; ΔDi-0S; ΔDi-4S; ΔDi-6S; ΔDi-diS(D); ΔDi-diS(E); ΔHexA(2S)α1–3GalNAc(6S); ΔHexA(α1–3)GalNAc; ΔHexAα1–3GalNAc(4S); ΔHexAα1–3GalNAc(4S, 6S); ΔHexAα1–3GalNAc(6S).
© 2013.