A chondroitin synthase-1 (ChSy-1) missense mutation in a patient with neuropathy impairs the elongation of chondroitin sulfate chains initiated by chondroitin N-acetylgalactosaminyltransferase-1 |
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Authors: | Tomomi Izumikawa Kazumasa Saigoh Jun Shimizu Shoji Tsuji Susumu Kusunoki Hiroshi Kitagawa |
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Affiliation: | 1. Department of Biochemistry, Kobe Pharmaceutical University, Higashinada-ku, Kobe 658-8558, Japan;2. Department of Neurology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan;3. Department of Neurology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan |
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Abstract: | BackgroundPreviously, 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.MethodsRecombinant wild-type chondroitin synthase-1 enzyme and the F362S mutant were expressed. These enzymes and cells expressing them were then characterized.ResultsThe 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.ConclusionsThe 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 significanceThe 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. |
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Keywords: | CS, chondroitin sulfate ChSy, chondroitin synthase ChGn, chondroitin GalNAcT ChPF, chondroitin polymerizing factor GalNAcT, N-acetylgalactosaminyltransferase GlcAT, glucuronyltransferase ΔDi-0S, ΔHexA(α1&ndash 3)GalNAc ΔDi-6S, ΔHexAα1&ndash 3GalNAc(6S) ΔDi-4S, ΔHexAα1&ndash 3GalNAc(4S) ΔDi-diSD, ΔHexA(2S)α1&ndash 3GalNAc(6S) ΔDi-diSE, ΔHexAα1&ndash 3GalNAc(4S, 6S) |
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