Chondroitin beta-1,4-N-acetylgalactosaminyltransferase-1 missense mutations are associated with neuropathies

Abstract

Chondroitin sulfate proteoglycans (CSPGs) in the peripheral nervous system likely participate as regulatory molecules in the process of axonal degeneration and regeneration. We investigated the chondroitin beta1,4-N-acetylgalactosaminyltransferase-1 (ChGn-1) gene in 114 patients affected with neuropathies including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, hereditary motor and sensory neuropathy (HMSN) and unknown etiology. The controls were 196 patients with other neurological diseases. We found novel missense mutations in two patients with neuropathy (Bell's palsy, unknown HMSN) in exons 5 (H234R) and 10 (M509R), respectively. None of the patients with other neurological diseases had either of these mutations. We then synthesized the two soluble forms of ChGn-1, containing each of the above mutations. Each of the soluble mutants was expressed in COS-1 cells and the mutant proteins were purified. The purified mutant proteins were used for western blotting analysis using an anti-ChGn-1 antibody and evaluated for glycosyltransferase activities. Although the expression of the ChGn-1 mutant proteins was confirmed by western blotting, they exhibited no N-acetylgalactosamineT-II activities. It is possible that these mutations are associated with the pathogenetic mechanisms of the peripheral neuropathies.

Using Sugar Remodeling to Study Chondroitin Sulfate Function

“…The causative mutations are H234R in exon 5 and M509R in exon 10, respectively. 42) Recombinant enzymes carrying the respective missense mutations exhibit no GalNAcT-II activity. 42) This finding indicates that defects in biosynthetic glycosyltransferases such as ChGn-1 may be associated with the pathogenesis of peripheral neuropathies because the genetic defects may compromise recovery from minor trauma.…”

“…42) Recombinant enzymes carrying the respective missense mutations exhibit no GalNAcT-II activity. 42) This finding indicates that defects in biosynthetic glycosyltransferases such as ChGn-1 may be associated with the pathogenesis of peripheral neuropathies because the genetic defects may compromise recovery from minor trauma. Moreover, a recent survey of ChSy-1 sequences among 310 patients with neurological disorders identified a novel missense mutation (F362S) in exon 3 of ChSy-1.…”

Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165

“…Their number is steadily growing with some 50 CDG having been reported (Jaeken 2010(Jaeken , 2011Rafiq et al 2011;Saigoh et al 2011;Baasanjar et al 2011;Hennet 2012). Most of them are multisystem diseases, but skeletal abnormalities are an important/predominant clinical feature in only about 20 % of the known CDG.…”

Human Genetic Disorders Caused by Mutations in Genes Encoding Biosynthetic Enzymes for Sulfated Glycosaminoglycans

“…Degeneration of myelin sheaths and/or axons causes paralytic amyotrophy predominantly involving distal limbs in association with hypo-or areflexia. The recombinant mutant proteins for H234R and M509R exhibit no GalNAcT-II activity, implying that these mutations in CSGALNACT1 and/or CS PGs may be associated with pathogenetic mechanisms of the peripheral neuropathies (69). To further understand the neuropathy involving CS, knock-out mice (Csgalnact1 Ϫ/Ϫ ) may be useful, although currently, the mice are reported to show only abnormal development in cartilage (71,72).…”

“…CSGALNACT1 Deficiency-Two possible mutations in the CSGALNACT1 gene, encoding a protein with GalNAcT-I and GalNAcT-II activities, are found in patients with Bell palsy and an unknown type of hereditary motor and sensory neuropathy (69). Hereditary motor and sensory neuropathies are heterogeneous neurodegenerative disorders characterized by a progressive loss of function in the peripheral sensory nerves (70).…”